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The Effect of Fexofenadine Hydrochloride on Productivity and Quality of Life in Patients With Chronic Idiopathic Urticaria
Lentigo Maligna (Melanoma In Situ) Treated With Imiquimod Cream 5%: 12 Case Reports
Classic and Atypical Spitz Nevi: Review of the Literature
Spitz nevi were first described in 1948.1 Spitz1 originally called these lesions benign juvenile melanoma. She was able to identify and describe a separate class of benign melanocytic neoplasms in children that were previously diagnosed and treated as melanoma.2 Prior to this discovery, the standard of care was to remove all suspicious pigmented lesions in children prior to adulthood to prevent possible malignant transformation.2,3 Today, Spitz nevus is the more commonly used term for benign juvenile melanoma because it is encountered occasionally in adults and the term melanoma carries a negative connotation.4 Other synonyms include juvenile melanoma, Spitz tumor, nevus of large spindle and/or epithelioid cells, and spindle cell and epithelioid nevus.3,5
Classic Spitz Nevus
Spitz nevi are uncommon. The approximate incidence is 7 per 100,000 people. Spitz nevi are more frequently found in children and adolescents but can occur in adults.6,7 Spitz nevi occur predominantly in the white population and slightly more often in females.4,8
A Spitz nevus can arise de novo or in association with an existing melanocytic nevus. The lesions can be asymptomatic or have a history of rapid but limited growth. Clinical features of Spitz nevi are well-circumscribed, symmetrical, small- to medium-sized firm papules with smooth discrete borders and a uniform color (typically pink or flesh colored).9 Spitz nevi can occur in various shapes. In a study of 211 cases of Spitz nevi, 19% were described as flat or uneven, 24% as polypoid, and 57% as plateau or elevated.7 Spitz nevi usually are found on the face, neck, or lower extremities but can occur anywhere on the body.7,9 Size is typically less than 6 mm (Figures 1 and 2).
PLEASE REFER TO THE PDF TO VIEW THE FIGURES
The classic Spitz nevus histologically consists of large spindle and/or epithelioid melanocytes arrayed as epidermal nests grouped in a vertical orientation (called "bunches of bananas" or "raining down pattern"), with clefting artifact at the perimeter (Figure 3).4,9,10 The nests are fairly uniform, nonconfluent, and evenly spaced. There is little or no pagetoid spread pattern. Epidermal changes include acanthosis, hypergranulosis, and hyperkeratosis. The intradermal pattern displays maturation, with single-file or single-unit arrays descending to the base. Eosinophilic Kamino bodies frequently are found along the dermoepidermal interface. Kamino bodies are globular clusters that represent apoptotic degenerative melanocytes (Figure 4). They stain positive with both periodic acid-Schiff and trichrome stains. At the dermal base, there is no mitosis, no pushing deep margins, and lack of significant pleomorphism. Little or no melanin is present.4,9,10 The classic Spitz nevus behaves in a benign manner.1 The differential diagnosis of the Spitz nevus includes pyogenic granuloma, mastocytoma, juvenile xanthogranuloma, and malignant melanoma.
PLEASE REFER TO THE PDF TO VIEW THE FIGURES
Atypical Spitz Nevus
The atypical Spitz nevus is difficult to formally define. Instead, it is loosely defined. An atypical Spitz nevus shares histologic features with the classic Spitz nevus, but it may have one or more atypical features, which can be characteristic of malignancy.10-12 Gross atypical features may include irregular shape, nonuniform color, large size, or ulcerations. Histologically, there can be one or more of the following features: pleomorphism; increased cellularity; loss of cellular cohesion; epidermal pagetoid spread; minimal epidermal changes; absence of Kamino bodies; lack of maturation in the intradermal pattern; high-grade nuclear atypia; high basal mitotic rate; pushing deep margins into the dermal base or subcutis; and nests variable in size, shape, and orientation.9,10,13
The behavior of any atypical Spitz nevus is unpredictable. There are case reports of metastasizing and malignant lesions with Spitz-like characteristics causing fatal outcomes.11,13 However, there also are studies that show Spitz nevi acting in a benign manner, even with a history of metastases.11,13-15 Some researchers try to explain this phenomenon by theorizing that Spitz nevi and melanoma exist along a continuum with the classic benign Spitz nevus at one end of the spectrum and the aggressive malignant melanoma at the opposite end, with a diverse range of atypical Spitz-like lesions with features of both in between.4,10-12,14 Other researchers refute this claim and view the unequivocal Spitz nevus as benign and unrelated to melanoma. They point out that many of these case reports of melanomas with Spitz-like features do not fit the diagnosis of the Spitz nevus.16
In general, the more features an atypical Spitz nevus shares with melanoma, the greater the risk for malignant behavior. In 1999, Spatz et al12 proposed formal and specific criteria for determining the risk for malignant behavior in atypical Spitz nevi in children. In the retrospective study, atypical features were used to define atypical Spitz nevi and grade their risk for metastasis. The 5 major factors were age, size, presence of ulceration, involvement of subcutaneous fat, and mitotic activity. Positive risk factors that increased the grade included age greater than 10 years, diameter greater than 10.0 mm, lesions with fat involvement, presence of ulceration, and dermal component mitotic activity greater than 5 mitoses/mm2. The higher the grade, the higher the risk for malignancy and metastasis.12 Since its publication, this grading system for categorizing atypical Spitz nevi has been put to use in a few case reports and studies.17,18 Additional prospective studies using these criteria will be helpful in determining the true clinical nature of atypical Spitz nevi in children, the usefulness of this grading system, and the possible application of this grading system in adults.
Problems Differentiating Classic and Atypical Spitz Nevi From Melanoma
Melanoma is a major part of the differential diagnosis of Spitz nevi. The classic Spitz nevus typically has a benign nature, while the atypical Spitz nevus displays unpredictable behavior that appears to be dependent on the degree of atypia.1,3,16 In contrast, melanoma is potentially fatal. Fortunately, Spitz nevi typically occur in children and the risk for having childhood melanoma is rare.6,8,19 Though risk is minimal, rare cases of melanoma have been reported in children.8,11,14,15,19-21 Therefore, making a correct diagnosis and ruling out melanoma is important.
Unfortunately, even with clinical and histologic guidelines, sometimes it is difficult to distinguish classic and atypical Spitz nevi from melanoma. The major problem is histologic overlap with Spitz nevi and melanoma. Many researchers have emphasized that there is no single discriminating factor for Spitz nevi and melanoma because virtually every trait of Spitz nevi has been described in melanoma.2,10,13,20,22,23 Results of multiple studies show variability among researchers on the analysis of melanocytic nevi and melanoma lesions, and the final diagnosis was subjective.5,22 In one retrospective study where clinical outcome was already known, 30 melanocytic lesions were evaluated independently by a panel of 10 dermatopathologists and categorized as either a typical Spitz nevus, atypical Spitz nevus, melanoma, tumor with unknown biologic potential, or other melanocytic lesion.5 The dermatopathologists were blinded to the clinical data. Evaluation of 17 Spitzoid lesions yielded no clear diagnostic consensus and a few lethal lesions were identified by most dermatopathologists as either typical or atypical Spitz nevi. The authors maintain that these results show that current objective criteria are deficient and inadequate to permit the discrimination of Spitz nevi with atypical features from melanoma.5
Given these histologic analysis limitations, many investigators are researching other tools and techniques that may help enhance diagnostic accuracy. Promising genetic analysis techniques include comparative genomic hybridization and fluorescent in situ hybridization.24 In one study,24 researchers compared Spitz nevi with primary cutaneous melanomas using comparative genomic hybridization and fluorescent in situ hybridization and discovered differences. In the study, Spitz nevi were found to have no chromosomal aberrations or gains in chromosome 11p or 7q21qter. In comparison, primary cutaneous melanomas had frequent chromosome deletions of chromosomes 9p, 10q, 6q, and 8p, and gains of chromosomes 7, 8, 6p, and 1q.24,25 Immunohistochemistry is another potential tool for improving diagnostic accuracy. Examples of promising immunohistochemical markers include antibody MIB-1,26-28 BCL-2,29 and anti-S100A6.30 Studies have shown that most melanomas are immunoreactive to MIB-1 and BCL-2, whereas Spitz nevi are not.26-29 Recently, anti-S100A6 protein also was shown to be a potential immunohistochemical marker to differentiate a Spitz nevus from melanoma.30 Anti-S100A6 is different from anti-S100 because it is more specific to a subclass of normal cell types and certain cancer cell lines. Investigators found strong, uniform, and diffuse S100A6 protein expression in the junctional and dermal components of all 42 Spitz nevi they studied versus weak and patchy S100A6 protein expression found mainly in the dermal component of 35 of 105 melanoma specimens they studied.30 Although these techniques show exceptional potential, further research will be required to prove their reliability.
Management of Classic and Atypical Spitz Nevi
There is controversy regarding the treatment of a classic Spitz nevus. Some investigators recommend conservative treatment because a Spitz nevus is benign. They find that the Spitz nevus may be removed or left alone.3 Others agree but would add that complete excision with clinical follow-up is appropriate if there are atypical features found on the Spitz nevus.16,23,31 Other investigators are more aggressive and recommend complete excision with clear margins of all Spitz nevi, unequivocal or not, because Spitz nevi have histologic overlap with melanoma, and recurrent lesions may present with pseudomelanomatous changes, which makes differentiation more difficult later.4,32 They conclude that the benefits of complete excision outweigh the risks of partial treatment.4 Regardless of how a Spitz nevus case is managed, regular follow-up with a dermatologist is recommended to look for any changes or recurrences suggestive of malignancy.
Currently, there are no available evidence-based recommendations with predictive value for the specific management of atypical Spitz nevi because their clinical course is mostly unknown and unpredictable. Most articles that do address the management of atypical Spitz nevi state that they should be completely excised and followed periodically.11,33 Murphy et al34 suggest that an atypical Spitz nevus should be completely excised to avoid the rare possibility of a melanoma masquerading as an atypical Spitz nevus. Furthermore, if the physician is suspicious of malignancy, it is recommended that the lesion be managed like a melanoma and be removed in accordance with current melanoma margin guidelines or with comprehensive margin control via Mohs micrographic surgery.34,35 Gurbuz et al17 stated that surgical margin excision, sentinel lymph node dissection, and clinical follow-up is recommended for atypical Spitz tumors. However, currently there are no prospective studies that have tested these various recommendations on atypical Spitz nevi management.
Within the last few years, sentinel lymph node biopsy (SLNB) has been proposed as a useful tool in the management of melanocytic neoplasms of uncertain behavior, such as the atypical Spitz nevus.36 Researchers recommend SLNB in atypical Spitz nevi greater than 1.0-mm thick.18,36,37 Supporters maintain that it increases the sensitivity of the diagnosis of melanoma (vs atypical Spitz nevus) and identifies patients who may potentially benefit from early lymph node dissection and/or adjuvant therapy. They state that a positive SLNB supports the diagnosis of malignancy and recommend that the lesion be treated aggressively. If the SLNB is negative, melanoma cannot be completely ruled out, but there is more reassurance that the lesion may be confined to the skin and can be completely removed by excision.18,36,37 Other advantages of SLNB include minimal invasiveness and morbidity. Some researchers believe melanocytic neoplasms in which melanoma cannot be ruled out should undergo complete surgical excision with wide margins in accordance with current melanoma guidelines,34,35 which can be as much as 3 cm.36,38 A negative SLNB offers the advantage of planning a complete excision of an atypical Spitz nevus that preserves surrounding margins and is cosmetically more acceptable,36 and avoiding the morbidity (ie, lymphedema, paresthesia) associated with regional or elective lymph node dissection.18
However, some researchers argue that a positive SLNB in an atypical Spitz nevus is not metastatic melanoma and point out articles that have shown classic and atypical Spitz nevi spreading to lymphatic vessels and lymph nodes but behaving in a benign manner.11,13,15,21,37 Therefore, more studies are needed to assess the prognostic significance of positive SLNB in atypical Spitz nevi.18
- Spitz S. Melanomas of childhood. Am J Pathol. 1948;24:591-609.
- Spatz A, Barnhill RL. The Spitz tumor 50 years later: revisiting a landmark contribution and unresolved controversy. J Am Acad Dermatol. 1999;40:223-228.
- Paniago-Pereira C, Maize JC, Ackerman AB. Nevus of large spindle and/or epithelioid cells (Spitz's nevus). Arch Dermatol. 1978;114:1811-1823.
- Casso EM, Grin-Jorgensen CM, Grant-Kels JM. Spitz nevi. J Am Acad Dermatol. 1992;27:901-913.
- Barnhill RL, Argenyi ZB, From L, et al. Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. Hum Pathol. 1999;30:513-520.
- Herreid PA, Shapiro PE. Age distribution of Spitz nevus vs malignant melanoma. Arch Dermatol. 1996;132:352-353.
- Weedon D, Little JH. Spindle and epithelioid cell nevi in children and adults. a review of 211 cases of the Spitz nevus. Cancer. 1977;40:217-225.
- Bader JL, Li FP, Olmstead PM, et al. Childhood malignant melanoma. incidence and etiology. Am J Pediatr Hematol Oncol. 1985;7:341-345.
- Elder DE, Murphy GF. Melanocytic tumors of the skin. In: Elder DE, Murphy GF, eds. Atlas of Tumor Pathology. Washington, DC: Armed Forces Institute of Pathology; 1990:40-57.
- Piepkorn M. On the nature of histologic observations: the case of the Spitz nevus. J Am Acad Dermatol. 1995;32:248-254.
- Barnhill RL, Flotte TJ, Fleischli M, et al. Cutaneous melanoma and atypical Spitz tumors in childhood. Cancer. 1995;76:1833-1845.
- Spatz A, Calonje E, Handfield-Jones S, et al. Spitz tumors in children: a grading system for risk stratification. Arch Dermatol. 1999;135:282-285.
- Smith KJ, Barrett TL, Skelton HG 3rd, et al. Spindle cell and epithelioid cell nevi with atypia and metastasis (malignant Spitz nevus). Am J Surg Pathol. 1989;13:931-939.
- Barnhill RL. Childhood melanoma. Semin Diagn Pathol. 1998;15:189-194.
- Melnik MK, Urdaneta LF, Al-Jurf AS, et al. Malignant melanoma in childhood and adolescence. Am Surg. 1986;52:142-147.
- Shapiro PE. Spitz nevi. J Am Acad Dermatol. 1993;29:667-668.
- Gurbuz Y, Apaydin R, Muezzinoglu B, et al. A current dilemma in histopathology: atypical spitz tumor or Spitzoid melanoma? Pediatr Dermatol. 2002;19:99-102.
- Lohmann CM, Coit DG, Brady MS, et al. Sentinel lymph node biopsy in patients with diagnostically controversial spitzoid melanocytic tumors. Am J Surg Pathol. 2002;26:47-55.
- Handfield-Jones SE, Smith NP. Malignant melanoma in childhood. Br J Dermatol. 1996;134:607-616.
- Crotty KA, McCarthy SW, Palmer AA, et al. Malignant melanoma in childhood: a clinicopathologic study of 13 cases and comparison with Spitz nevi. World J Surg. 1992;16:179-185.
- Lerman RI, Murray D, O'Hara JM, et al. Malignant melanoma of childhood. a clinicopathologic study and a report of 12 cases. Cancer. 1970;25:436-449.
- Farmer ER, Gonin R, Hanna MP. Discordance in the histopathologic diagnosis of melanoma and melano-cytic nevi between expert pathologists. Hum Pathol.1996;27:528-531.
- Shimek CM, Golitz LE. The golden anniversary of the Spitz nevus. Arch Dermatol. 1999;135:333-335.
- Bastian BC, Wesselmann U, Pinkel D, et al. Molecular cytogenetic analysis of Spitz nevi shows clear differences to melanoma. J Invest Dermatol.1999; 113:1065-1069.
- Bastian BC, LeBoit PE, Hamm H, et al. Chromo-somal gains and losses in primary cutaneous melanomas detected by comparative genomic hybridization. Cancer Res.1998;58:2170-2175.
- Bergman R, Malkin L, Sabo E, et al. MIB-1 mono-clonal antibody to determine proliferative activity of Ki-67 antigen as an adjunct to the histopathologic dif-ferential diagnosis of Spitz nevi. J Am Acad Dermatol. 2001; 44:500-504.
- Li LX, Crotty KA, McCarthy SW, et al. A zonal com-parison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions. Am J Dermatopathol. 2000;22:489-495.
- McNutt NS, Urmacher C, Hakimian J, et al. Nevoid malignant melanoma: morphologicpatterns and immu-nohistochemical reactivity. J Cutan Pathol.1995;22:502-517.
- Kanter-Lewensohn L, Hedblad MA, Wejde J, et al. Immu-nohistochemical markers for distinguishing Spitz nevi from malignant melanomas. Mod Pathol.1997;10:917-920.
- Ribé A, McNutt NS. S100A6 protein expression is different in spitz nevi and melanomas. Mod Pathol.2003;16:505-511.
- Kaye VN, Dehner LP. Spindle and epithelioid cell nevus (Spitz nevus). natural history following biopsy. Arch Dermatol.1990;126:1581-1583.
- Omura EF, Kheir SM. Recurrent Spitz’s nevus. Am J. Dermatopathol.1984;6(suppl): 207212.
- Zaenglein AL, Heintz P, Kamino H, et al. Congenital Spitz nevus clinically mimicking melanoma. J Am Acad Dermatol.2002;47:441-444.
- Murphy ME, Boyer JD, Stashower ME, et al. The surgical management of Spitz nevi. Dermatol Surg. 2002;28:1065-1069.
- Zitelli JA, Brown C, Hanusa BH. Mohs micrographic surgery for the treatment of primary cutaneous melanoma. J Am Acad Dermatol. 1997;37:236-245.
- Kelley SW, Cockerell CJ. Sentinel lymph node biopsy as an adjunct to management of histologically difficult to diagnose melanocytic lesions: a proposal. J Am Acad Dermatol. 2000;42:527-530.
- Su LD, Fullen DR, Sondak VK, et al. Sentinel lymph node biopsy for patients with problematic spitzoid melanocytic lesions: a report on 18 patients. Cancer. 2003;97:499-507.
- Martinez JC, Otley CC. The management of melanoma and nonmelanoma skin cancer: a review for the primary care physician. Mayo Clin Proc. 2001;76:1253-1265.
Spitz nevi were first described in 1948.1 Spitz1 originally called these lesions benign juvenile melanoma. She was able to identify and describe a separate class of benign melanocytic neoplasms in children that were previously diagnosed and treated as melanoma.2 Prior to this discovery, the standard of care was to remove all suspicious pigmented lesions in children prior to adulthood to prevent possible malignant transformation.2,3 Today, Spitz nevus is the more commonly used term for benign juvenile melanoma because it is encountered occasionally in adults and the term melanoma carries a negative connotation.4 Other synonyms include juvenile melanoma, Spitz tumor, nevus of large spindle and/or epithelioid cells, and spindle cell and epithelioid nevus.3,5
Classic Spitz Nevus
Spitz nevi are uncommon. The approximate incidence is 7 per 100,000 people. Spitz nevi are more frequently found in children and adolescents but can occur in adults.6,7 Spitz nevi occur predominantly in the white population and slightly more often in females.4,8
A Spitz nevus can arise de novo or in association with an existing melanocytic nevus. The lesions can be asymptomatic or have a history of rapid but limited growth. Clinical features of Spitz nevi are well-circumscribed, symmetrical, small- to medium-sized firm papules with smooth discrete borders and a uniform color (typically pink or flesh colored).9 Spitz nevi can occur in various shapes. In a study of 211 cases of Spitz nevi, 19% were described as flat or uneven, 24% as polypoid, and 57% as plateau or elevated.7 Spitz nevi usually are found on the face, neck, or lower extremities but can occur anywhere on the body.7,9 Size is typically less than 6 mm (Figures 1 and 2).
PLEASE REFER TO THE PDF TO VIEW THE FIGURES
The classic Spitz nevus histologically consists of large spindle and/or epithelioid melanocytes arrayed as epidermal nests grouped in a vertical orientation (called "bunches of bananas" or "raining down pattern"), with clefting artifact at the perimeter (Figure 3).4,9,10 The nests are fairly uniform, nonconfluent, and evenly spaced. There is little or no pagetoid spread pattern. Epidermal changes include acanthosis, hypergranulosis, and hyperkeratosis. The intradermal pattern displays maturation, with single-file or single-unit arrays descending to the base. Eosinophilic Kamino bodies frequently are found along the dermoepidermal interface. Kamino bodies are globular clusters that represent apoptotic degenerative melanocytes (Figure 4). They stain positive with both periodic acid-Schiff and trichrome stains. At the dermal base, there is no mitosis, no pushing deep margins, and lack of significant pleomorphism. Little or no melanin is present.4,9,10 The classic Spitz nevus behaves in a benign manner.1 The differential diagnosis of the Spitz nevus includes pyogenic granuloma, mastocytoma, juvenile xanthogranuloma, and malignant melanoma.
PLEASE REFER TO THE PDF TO VIEW THE FIGURES
Atypical Spitz Nevus
The atypical Spitz nevus is difficult to formally define. Instead, it is loosely defined. An atypical Spitz nevus shares histologic features with the classic Spitz nevus, but it may have one or more atypical features, which can be characteristic of malignancy.10-12 Gross atypical features may include irregular shape, nonuniform color, large size, or ulcerations. Histologically, there can be one or more of the following features: pleomorphism; increased cellularity; loss of cellular cohesion; epidermal pagetoid spread; minimal epidermal changes; absence of Kamino bodies; lack of maturation in the intradermal pattern; high-grade nuclear atypia; high basal mitotic rate; pushing deep margins into the dermal base or subcutis; and nests variable in size, shape, and orientation.9,10,13
The behavior of any atypical Spitz nevus is unpredictable. There are case reports of metastasizing and malignant lesions with Spitz-like characteristics causing fatal outcomes.11,13 However, there also are studies that show Spitz nevi acting in a benign manner, even with a history of metastases.11,13-15 Some researchers try to explain this phenomenon by theorizing that Spitz nevi and melanoma exist along a continuum with the classic benign Spitz nevus at one end of the spectrum and the aggressive malignant melanoma at the opposite end, with a diverse range of atypical Spitz-like lesions with features of both in between.4,10-12,14 Other researchers refute this claim and view the unequivocal Spitz nevus as benign and unrelated to melanoma. They point out that many of these case reports of melanomas with Spitz-like features do not fit the diagnosis of the Spitz nevus.16
In general, the more features an atypical Spitz nevus shares with melanoma, the greater the risk for malignant behavior. In 1999, Spatz et al12 proposed formal and specific criteria for determining the risk for malignant behavior in atypical Spitz nevi in children. In the retrospective study, atypical features were used to define atypical Spitz nevi and grade their risk for metastasis. The 5 major factors were age, size, presence of ulceration, involvement of subcutaneous fat, and mitotic activity. Positive risk factors that increased the grade included age greater than 10 years, diameter greater than 10.0 mm, lesions with fat involvement, presence of ulceration, and dermal component mitotic activity greater than 5 mitoses/mm2. The higher the grade, the higher the risk for malignancy and metastasis.12 Since its publication, this grading system for categorizing atypical Spitz nevi has been put to use in a few case reports and studies.17,18 Additional prospective studies using these criteria will be helpful in determining the true clinical nature of atypical Spitz nevi in children, the usefulness of this grading system, and the possible application of this grading system in adults.
Problems Differentiating Classic and Atypical Spitz Nevi From Melanoma
Melanoma is a major part of the differential diagnosis of Spitz nevi. The classic Spitz nevus typically has a benign nature, while the atypical Spitz nevus displays unpredictable behavior that appears to be dependent on the degree of atypia.1,3,16 In contrast, melanoma is potentially fatal. Fortunately, Spitz nevi typically occur in children and the risk for having childhood melanoma is rare.6,8,19 Though risk is minimal, rare cases of melanoma have been reported in children.8,11,14,15,19-21 Therefore, making a correct diagnosis and ruling out melanoma is important.
Unfortunately, even with clinical and histologic guidelines, sometimes it is difficult to distinguish classic and atypical Spitz nevi from melanoma. The major problem is histologic overlap with Spitz nevi and melanoma. Many researchers have emphasized that there is no single discriminating factor for Spitz nevi and melanoma because virtually every trait of Spitz nevi has been described in melanoma.2,10,13,20,22,23 Results of multiple studies show variability among researchers on the analysis of melanocytic nevi and melanoma lesions, and the final diagnosis was subjective.5,22 In one retrospective study where clinical outcome was already known, 30 melanocytic lesions were evaluated independently by a panel of 10 dermatopathologists and categorized as either a typical Spitz nevus, atypical Spitz nevus, melanoma, tumor with unknown biologic potential, or other melanocytic lesion.5 The dermatopathologists were blinded to the clinical data. Evaluation of 17 Spitzoid lesions yielded no clear diagnostic consensus and a few lethal lesions were identified by most dermatopathologists as either typical or atypical Spitz nevi. The authors maintain that these results show that current objective criteria are deficient and inadequate to permit the discrimination of Spitz nevi with atypical features from melanoma.5
Given these histologic analysis limitations, many investigators are researching other tools and techniques that may help enhance diagnostic accuracy. Promising genetic analysis techniques include comparative genomic hybridization and fluorescent in situ hybridization.24 In one study,24 researchers compared Spitz nevi with primary cutaneous melanomas using comparative genomic hybridization and fluorescent in situ hybridization and discovered differences. In the study, Spitz nevi were found to have no chromosomal aberrations or gains in chromosome 11p or 7q21qter. In comparison, primary cutaneous melanomas had frequent chromosome deletions of chromosomes 9p, 10q, 6q, and 8p, and gains of chromosomes 7, 8, 6p, and 1q.24,25 Immunohistochemistry is another potential tool for improving diagnostic accuracy. Examples of promising immunohistochemical markers include antibody MIB-1,26-28 BCL-2,29 and anti-S100A6.30 Studies have shown that most melanomas are immunoreactive to MIB-1 and BCL-2, whereas Spitz nevi are not.26-29 Recently, anti-S100A6 protein also was shown to be a potential immunohistochemical marker to differentiate a Spitz nevus from melanoma.30 Anti-S100A6 is different from anti-S100 because it is more specific to a subclass of normal cell types and certain cancer cell lines. Investigators found strong, uniform, and diffuse S100A6 protein expression in the junctional and dermal components of all 42 Spitz nevi they studied versus weak and patchy S100A6 protein expression found mainly in the dermal component of 35 of 105 melanoma specimens they studied.30 Although these techniques show exceptional potential, further research will be required to prove their reliability.
Management of Classic and Atypical Spitz Nevi
There is controversy regarding the treatment of a classic Spitz nevus. Some investigators recommend conservative treatment because a Spitz nevus is benign. They find that the Spitz nevus may be removed or left alone.3 Others agree but would add that complete excision with clinical follow-up is appropriate if there are atypical features found on the Spitz nevus.16,23,31 Other investigators are more aggressive and recommend complete excision with clear margins of all Spitz nevi, unequivocal or not, because Spitz nevi have histologic overlap with melanoma, and recurrent lesions may present with pseudomelanomatous changes, which makes differentiation more difficult later.4,32 They conclude that the benefits of complete excision outweigh the risks of partial treatment.4 Regardless of how a Spitz nevus case is managed, regular follow-up with a dermatologist is recommended to look for any changes or recurrences suggestive of malignancy.
Currently, there are no available evidence-based recommendations with predictive value for the specific management of atypical Spitz nevi because their clinical course is mostly unknown and unpredictable. Most articles that do address the management of atypical Spitz nevi state that they should be completely excised and followed periodically.11,33 Murphy et al34 suggest that an atypical Spitz nevus should be completely excised to avoid the rare possibility of a melanoma masquerading as an atypical Spitz nevus. Furthermore, if the physician is suspicious of malignancy, it is recommended that the lesion be managed like a melanoma and be removed in accordance with current melanoma margin guidelines or with comprehensive margin control via Mohs micrographic surgery.34,35 Gurbuz et al17 stated that surgical margin excision, sentinel lymph node dissection, and clinical follow-up is recommended for atypical Spitz tumors. However, currently there are no prospective studies that have tested these various recommendations on atypical Spitz nevi management.
Within the last few years, sentinel lymph node biopsy (SLNB) has been proposed as a useful tool in the management of melanocytic neoplasms of uncertain behavior, such as the atypical Spitz nevus.36 Researchers recommend SLNB in atypical Spitz nevi greater than 1.0-mm thick.18,36,37 Supporters maintain that it increases the sensitivity of the diagnosis of melanoma (vs atypical Spitz nevus) and identifies patients who may potentially benefit from early lymph node dissection and/or adjuvant therapy. They state that a positive SLNB supports the diagnosis of malignancy and recommend that the lesion be treated aggressively. If the SLNB is negative, melanoma cannot be completely ruled out, but there is more reassurance that the lesion may be confined to the skin and can be completely removed by excision.18,36,37 Other advantages of SLNB include minimal invasiveness and morbidity. Some researchers believe melanocytic neoplasms in which melanoma cannot be ruled out should undergo complete surgical excision with wide margins in accordance with current melanoma guidelines,34,35 which can be as much as 3 cm.36,38 A negative SLNB offers the advantage of planning a complete excision of an atypical Spitz nevus that preserves surrounding margins and is cosmetically more acceptable,36 and avoiding the morbidity (ie, lymphedema, paresthesia) associated with regional or elective lymph node dissection.18
However, some researchers argue that a positive SLNB in an atypical Spitz nevus is not metastatic melanoma and point out articles that have shown classic and atypical Spitz nevi spreading to lymphatic vessels and lymph nodes but behaving in a benign manner.11,13,15,21,37 Therefore, more studies are needed to assess the prognostic significance of positive SLNB in atypical Spitz nevi.18
Spitz nevi were first described in 1948.1 Spitz1 originally called these lesions benign juvenile melanoma. She was able to identify and describe a separate class of benign melanocytic neoplasms in children that were previously diagnosed and treated as melanoma.2 Prior to this discovery, the standard of care was to remove all suspicious pigmented lesions in children prior to adulthood to prevent possible malignant transformation.2,3 Today, Spitz nevus is the more commonly used term for benign juvenile melanoma because it is encountered occasionally in adults and the term melanoma carries a negative connotation.4 Other synonyms include juvenile melanoma, Spitz tumor, nevus of large spindle and/or epithelioid cells, and spindle cell and epithelioid nevus.3,5
Classic Spitz Nevus
Spitz nevi are uncommon. The approximate incidence is 7 per 100,000 people. Spitz nevi are more frequently found in children and adolescents but can occur in adults.6,7 Spitz nevi occur predominantly in the white population and slightly more often in females.4,8
A Spitz nevus can arise de novo or in association with an existing melanocytic nevus. The lesions can be asymptomatic or have a history of rapid but limited growth. Clinical features of Spitz nevi are well-circumscribed, symmetrical, small- to medium-sized firm papules with smooth discrete borders and a uniform color (typically pink or flesh colored).9 Spitz nevi can occur in various shapes. In a study of 211 cases of Spitz nevi, 19% were described as flat or uneven, 24% as polypoid, and 57% as plateau or elevated.7 Spitz nevi usually are found on the face, neck, or lower extremities but can occur anywhere on the body.7,9 Size is typically less than 6 mm (Figures 1 and 2).
PLEASE REFER TO THE PDF TO VIEW THE FIGURES
The classic Spitz nevus histologically consists of large spindle and/or epithelioid melanocytes arrayed as epidermal nests grouped in a vertical orientation (called "bunches of bananas" or "raining down pattern"), with clefting artifact at the perimeter (Figure 3).4,9,10 The nests are fairly uniform, nonconfluent, and evenly spaced. There is little or no pagetoid spread pattern. Epidermal changes include acanthosis, hypergranulosis, and hyperkeratosis. The intradermal pattern displays maturation, with single-file or single-unit arrays descending to the base. Eosinophilic Kamino bodies frequently are found along the dermoepidermal interface. Kamino bodies are globular clusters that represent apoptotic degenerative melanocytes (Figure 4). They stain positive with both periodic acid-Schiff and trichrome stains. At the dermal base, there is no mitosis, no pushing deep margins, and lack of significant pleomorphism. Little or no melanin is present.4,9,10 The classic Spitz nevus behaves in a benign manner.1 The differential diagnosis of the Spitz nevus includes pyogenic granuloma, mastocytoma, juvenile xanthogranuloma, and malignant melanoma.
PLEASE REFER TO THE PDF TO VIEW THE FIGURES
Atypical Spitz Nevus
The atypical Spitz nevus is difficult to formally define. Instead, it is loosely defined. An atypical Spitz nevus shares histologic features with the classic Spitz nevus, but it may have one or more atypical features, which can be characteristic of malignancy.10-12 Gross atypical features may include irregular shape, nonuniform color, large size, or ulcerations. Histologically, there can be one or more of the following features: pleomorphism; increased cellularity; loss of cellular cohesion; epidermal pagetoid spread; minimal epidermal changes; absence of Kamino bodies; lack of maturation in the intradermal pattern; high-grade nuclear atypia; high basal mitotic rate; pushing deep margins into the dermal base or subcutis; and nests variable in size, shape, and orientation.9,10,13
The behavior of any atypical Spitz nevus is unpredictable. There are case reports of metastasizing and malignant lesions with Spitz-like characteristics causing fatal outcomes.11,13 However, there also are studies that show Spitz nevi acting in a benign manner, even with a history of metastases.11,13-15 Some researchers try to explain this phenomenon by theorizing that Spitz nevi and melanoma exist along a continuum with the classic benign Spitz nevus at one end of the spectrum and the aggressive malignant melanoma at the opposite end, with a diverse range of atypical Spitz-like lesions with features of both in between.4,10-12,14 Other researchers refute this claim and view the unequivocal Spitz nevus as benign and unrelated to melanoma. They point out that many of these case reports of melanomas with Spitz-like features do not fit the diagnosis of the Spitz nevus.16
In general, the more features an atypical Spitz nevus shares with melanoma, the greater the risk for malignant behavior. In 1999, Spatz et al12 proposed formal and specific criteria for determining the risk for malignant behavior in atypical Spitz nevi in children. In the retrospective study, atypical features were used to define atypical Spitz nevi and grade their risk for metastasis. The 5 major factors were age, size, presence of ulceration, involvement of subcutaneous fat, and mitotic activity. Positive risk factors that increased the grade included age greater than 10 years, diameter greater than 10.0 mm, lesions with fat involvement, presence of ulceration, and dermal component mitotic activity greater than 5 mitoses/mm2. The higher the grade, the higher the risk for malignancy and metastasis.12 Since its publication, this grading system for categorizing atypical Spitz nevi has been put to use in a few case reports and studies.17,18 Additional prospective studies using these criteria will be helpful in determining the true clinical nature of atypical Spitz nevi in children, the usefulness of this grading system, and the possible application of this grading system in adults.
Problems Differentiating Classic and Atypical Spitz Nevi From Melanoma
Melanoma is a major part of the differential diagnosis of Spitz nevi. The classic Spitz nevus typically has a benign nature, while the atypical Spitz nevus displays unpredictable behavior that appears to be dependent on the degree of atypia.1,3,16 In contrast, melanoma is potentially fatal. Fortunately, Spitz nevi typically occur in children and the risk for having childhood melanoma is rare.6,8,19 Though risk is minimal, rare cases of melanoma have been reported in children.8,11,14,15,19-21 Therefore, making a correct diagnosis and ruling out melanoma is important.
Unfortunately, even with clinical and histologic guidelines, sometimes it is difficult to distinguish classic and atypical Spitz nevi from melanoma. The major problem is histologic overlap with Spitz nevi and melanoma. Many researchers have emphasized that there is no single discriminating factor for Spitz nevi and melanoma because virtually every trait of Spitz nevi has been described in melanoma.2,10,13,20,22,23 Results of multiple studies show variability among researchers on the analysis of melanocytic nevi and melanoma lesions, and the final diagnosis was subjective.5,22 In one retrospective study where clinical outcome was already known, 30 melanocytic lesions were evaluated independently by a panel of 10 dermatopathologists and categorized as either a typical Spitz nevus, atypical Spitz nevus, melanoma, tumor with unknown biologic potential, or other melanocytic lesion.5 The dermatopathologists were blinded to the clinical data. Evaluation of 17 Spitzoid lesions yielded no clear diagnostic consensus and a few lethal lesions were identified by most dermatopathologists as either typical or atypical Spitz nevi. The authors maintain that these results show that current objective criteria are deficient and inadequate to permit the discrimination of Spitz nevi with atypical features from melanoma.5
Given these histologic analysis limitations, many investigators are researching other tools and techniques that may help enhance diagnostic accuracy. Promising genetic analysis techniques include comparative genomic hybridization and fluorescent in situ hybridization.24 In one study,24 researchers compared Spitz nevi with primary cutaneous melanomas using comparative genomic hybridization and fluorescent in situ hybridization and discovered differences. In the study, Spitz nevi were found to have no chromosomal aberrations or gains in chromosome 11p or 7q21qter. In comparison, primary cutaneous melanomas had frequent chromosome deletions of chromosomes 9p, 10q, 6q, and 8p, and gains of chromosomes 7, 8, 6p, and 1q.24,25 Immunohistochemistry is another potential tool for improving diagnostic accuracy. Examples of promising immunohistochemical markers include antibody MIB-1,26-28 BCL-2,29 and anti-S100A6.30 Studies have shown that most melanomas are immunoreactive to MIB-1 and BCL-2, whereas Spitz nevi are not.26-29 Recently, anti-S100A6 protein also was shown to be a potential immunohistochemical marker to differentiate a Spitz nevus from melanoma.30 Anti-S100A6 is different from anti-S100 because it is more specific to a subclass of normal cell types and certain cancer cell lines. Investigators found strong, uniform, and diffuse S100A6 protein expression in the junctional and dermal components of all 42 Spitz nevi they studied versus weak and patchy S100A6 protein expression found mainly in the dermal component of 35 of 105 melanoma specimens they studied.30 Although these techniques show exceptional potential, further research will be required to prove their reliability.
Management of Classic and Atypical Spitz Nevi
There is controversy regarding the treatment of a classic Spitz nevus. Some investigators recommend conservative treatment because a Spitz nevus is benign. They find that the Spitz nevus may be removed or left alone.3 Others agree but would add that complete excision with clinical follow-up is appropriate if there are atypical features found on the Spitz nevus.16,23,31 Other investigators are more aggressive and recommend complete excision with clear margins of all Spitz nevi, unequivocal or not, because Spitz nevi have histologic overlap with melanoma, and recurrent lesions may present with pseudomelanomatous changes, which makes differentiation more difficult later.4,32 They conclude that the benefits of complete excision outweigh the risks of partial treatment.4 Regardless of how a Spitz nevus case is managed, regular follow-up with a dermatologist is recommended to look for any changes or recurrences suggestive of malignancy.
Currently, there are no available evidence-based recommendations with predictive value for the specific management of atypical Spitz nevi because their clinical course is mostly unknown and unpredictable. Most articles that do address the management of atypical Spitz nevi state that they should be completely excised and followed periodically.11,33 Murphy et al34 suggest that an atypical Spitz nevus should be completely excised to avoid the rare possibility of a melanoma masquerading as an atypical Spitz nevus. Furthermore, if the physician is suspicious of malignancy, it is recommended that the lesion be managed like a melanoma and be removed in accordance with current melanoma margin guidelines or with comprehensive margin control via Mohs micrographic surgery.34,35 Gurbuz et al17 stated that surgical margin excision, sentinel lymph node dissection, and clinical follow-up is recommended for atypical Spitz tumors. However, currently there are no prospective studies that have tested these various recommendations on atypical Spitz nevi management.
Within the last few years, sentinel lymph node biopsy (SLNB) has been proposed as a useful tool in the management of melanocytic neoplasms of uncertain behavior, such as the atypical Spitz nevus.36 Researchers recommend SLNB in atypical Spitz nevi greater than 1.0-mm thick.18,36,37 Supporters maintain that it increases the sensitivity of the diagnosis of melanoma (vs atypical Spitz nevus) and identifies patients who may potentially benefit from early lymph node dissection and/or adjuvant therapy. They state that a positive SLNB supports the diagnosis of malignancy and recommend that the lesion be treated aggressively. If the SLNB is negative, melanoma cannot be completely ruled out, but there is more reassurance that the lesion may be confined to the skin and can be completely removed by excision.18,36,37 Other advantages of SLNB include minimal invasiveness and morbidity. Some researchers believe melanocytic neoplasms in which melanoma cannot be ruled out should undergo complete surgical excision with wide margins in accordance with current melanoma guidelines,34,35 which can be as much as 3 cm.36,38 A negative SLNB offers the advantage of planning a complete excision of an atypical Spitz nevus that preserves surrounding margins and is cosmetically more acceptable,36 and avoiding the morbidity (ie, lymphedema, paresthesia) associated with regional or elective lymph node dissection.18
However, some researchers argue that a positive SLNB in an atypical Spitz nevus is not metastatic melanoma and point out articles that have shown classic and atypical Spitz nevi spreading to lymphatic vessels and lymph nodes but behaving in a benign manner.11,13,15,21,37 Therefore, more studies are needed to assess the prognostic significance of positive SLNB in atypical Spitz nevi.18
- Spitz S. Melanomas of childhood. Am J Pathol. 1948;24:591-609.
- Spatz A, Barnhill RL. The Spitz tumor 50 years later: revisiting a landmark contribution and unresolved controversy. J Am Acad Dermatol. 1999;40:223-228.
- Paniago-Pereira C, Maize JC, Ackerman AB. Nevus of large spindle and/or epithelioid cells (Spitz's nevus). Arch Dermatol. 1978;114:1811-1823.
- Casso EM, Grin-Jorgensen CM, Grant-Kels JM. Spitz nevi. J Am Acad Dermatol. 1992;27:901-913.
- Barnhill RL, Argenyi ZB, From L, et al. Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. Hum Pathol. 1999;30:513-520.
- Herreid PA, Shapiro PE. Age distribution of Spitz nevus vs malignant melanoma. Arch Dermatol. 1996;132:352-353.
- Weedon D, Little JH. Spindle and epithelioid cell nevi in children and adults. a review of 211 cases of the Spitz nevus. Cancer. 1977;40:217-225.
- Bader JL, Li FP, Olmstead PM, et al. Childhood malignant melanoma. incidence and etiology. Am J Pediatr Hematol Oncol. 1985;7:341-345.
- Elder DE, Murphy GF. Melanocytic tumors of the skin. In: Elder DE, Murphy GF, eds. Atlas of Tumor Pathology. Washington, DC: Armed Forces Institute of Pathology; 1990:40-57.
- Piepkorn M. On the nature of histologic observations: the case of the Spitz nevus. J Am Acad Dermatol. 1995;32:248-254.
- Barnhill RL, Flotte TJ, Fleischli M, et al. Cutaneous melanoma and atypical Spitz tumors in childhood. Cancer. 1995;76:1833-1845.
- Spatz A, Calonje E, Handfield-Jones S, et al. Spitz tumors in children: a grading system for risk stratification. Arch Dermatol. 1999;135:282-285.
- Smith KJ, Barrett TL, Skelton HG 3rd, et al. Spindle cell and epithelioid cell nevi with atypia and metastasis (malignant Spitz nevus). Am J Surg Pathol. 1989;13:931-939.
- Barnhill RL. Childhood melanoma. Semin Diagn Pathol. 1998;15:189-194.
- Melnik MK, Urdaneta LF, Al-Jurf AS, et al. Malignant melanoma in childhood and adolescence. Am Surg. 1986;52:142-147.
- Shapiro PE. Spitz nevi. J Am Acad Dermatol. 1993;29:667-668.
- Gurbuz Y, Apaydin R, Muezzinoglu B, et al. A current dilemma in histopathology: atypical spitz tumor or Spitzoid melanoma? Pediatr Dermatol. 2002;19:99-102.
- Lohmann CM, Coit DG, Brady MS, et al. Sentinel lymph node biopsy in patients with diagnostically controversial spitzoid melanocytic tumors. Am J Surg Pathol. 2002;26:47-55.
- Handfield-Jones SE, Smith NP. Malignant melanoma in childhood. Br J Dermatol. 1996;134:607-616.
- Crotty KA, McCarthy SW, Palmer AA, et al. Malignant melanoma in childhood: a clinicopathologic study of 13 cases and comparison with Spitz nevi. World J Surg. 1992;16:179-185.
- Lerman RI, Murray D, O'Hara JM, et al. Malignant melanoma of childhood. a clinicopathologic study and a report of 12 cases. Cancer. 1970;25:436-449.
- Farmer ER, Gonin R, Hanna MP. Discordance in the histopathologic diagnosis of melanoma and melano-cytic nevi between expert pathologists. Hum Pathol.1996;27:528-531.
- Shimek CM, Golitz LE. The golden anniversary of the Spitz nevus. Arch Dermatol. 1999;135:333-335.
- Bastian BC, Wesselmann U, Pinkel D, et al. Molecular cytogenetic analysis of Spitz nevi shows clear differences to melanoma. J Invest Dermatol.1999; 113:1065-1069.
- Bastian BC, LeBoit PE, Hamm H, et al. Chromo-somal gains and losses in primary cutaneous melanomas detected by comparative genomic hybridization. Cancer Res.1998;58:2170-2175.
- Bergman R, Malkin L, Sabo E, et al. MIB-1 mono-clonal antibody to determine proliferative activity of Ki-67 antigen as an adjunct to the histopathologic dif-ferential diagnosis of Spitz nevi. J Am Acad Dermatol. 2001; 44:500-504.
- Li LX, Crotty KA, McCarthy SW, et al. A zonal com-parison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions. Am J Dermatopathol. 2000;22:489-495.
- McNutt NS, Urmacher C, Hakimian J, et al. Nevoid malignant melanoma: morphologicpatterns and immu-nohistochemical reactivity. J Cutan Pathol.1995;22:502-517.
- Kanter-Lewensohn L, Hedblad MA, Wejde J, et al. Immu-nohistochemical markers for distinguishing Spitz nevi from malignant melanomas. Mod Pathol.1997;10:917-920.
- Ribé A, McNutt NS. S100A6 protein expression is different in spitz nevi and melanomas. Mod Pathol.2003;16:505-511.
- Kaye VN, Dehner LP. Spindle and epithelioid cell nevus (Spitz nevus). natural history following biopsy. Arch Dermatol.1990;126:1581-1583.
- Omura EF, Kheir SM. Recurrent Spitz’s nevus. Am J. Dermatopathol.1984;6(suppl): 207212.
- Zaenglein AL, Heintz P, Kamino H, et al. Congenital Spitz nevus clinically mimicking melanoma. J Am Acad Dermatol.2002;47:441-444.
- Murphy ME, Boyer JD, Stashower ME, et al. The surgical management of Spitz nevi. Dermatol Surg. 2002;28:1065-1069.
- Zitelli JA, Brown C, Hanusa BH. Mohs micrographic surgery for the treatment of primary cutaneous melanoma. J Am Acad Dermatol. 1997;37:236-245.
- Kelley SW, Cockerell CJ. Sentinel lymph node biopsy as an adjunct to management of histologically difficult to diagnose melanocytic lesions: a proposal. J Am Acad Dermatol. 2000;42:527-530.
- Su LD, Fullen DR, Sondak VK, et al. Sentinel lymph node biopsy for patients with problematic spitzoid melanocytic lesions: a report on 18 patients. Cancer. 2003;97:499-507.
- Martinez JC, Otley CC. The management of melanoma and nonmelanoma skin cancer: a review for the primary care physician. Mayo Clin Proc. 2001;76:1253-1265.
- Spitz S. Melanomas of childhood. Am J Pathol. 1948;24:591-609.
- Spatz A, Barnhill RL. The Spitz tumor 50 years later: revisiting a landmark contribution and unresolved controversy. J Am Acad Dermatol. 1999;40:223-228.
- Paniago-Pereira C, Maize JC, Ackerman AB. Nevus of large spindle and/or epithelioid cells (Spitz's nevus). Arch Dermatol. 1978;114:1811-1823.
- Casso EM, Grin-Jorgensen CM, Grant-Kels JM. Spitz nevi. J Am Acad Dermatol. 1992;27:901-913.
- Barnhill RL, Argenyi ZB, From L, et al. Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. Hum Pathol. 1999;30:513-520.
- Herreid PA, Shapiro PE. Age distribution of Spitz nevus vs malignant melanoma. Arch Dermatol. 1996;132:352-353.
- Weedon D, Little JH. Spindle and epithelioid cell nevi in children and adults. a review of 211 cases of the Spitz nevus. Cancer. 1977;40:217-225.
- Bader JL, Li FP, Olmstead PM, et al. Childhood malignant melanoma. incidence and etiology. Am J Pediatr Hematol Oncol. 1985;7:341-345.
- Elder DE, Murphy GF. Melanocytic tumors of the skin. In: Elder DE, Murphy GF, eds. Atlas of Tumor Pathology. Washington, DC: Armed Forces Institute of Pathology; 1990:40-57.
- Piepkorn M. On the nature of histologic observations: the case of the Spitz nevus. J Am Acad Dermatol. 1995;32:248-254.
- Barnhill RL, Flotte TJ, Fleischli M, et al. Cutaneous melanoma and atypical Spitz tumors in childhood. Cancer. 1995;76:1833-1845.
- Spatz A, Calonje E, Handfield-Jones S, et al. Spitz tumors in children: a grading system for risk stratification. Arch Dermatol. 1999;135:282-285.
- Smith KJ, Barrett TL, Skelton HG 3rd, et al. Spindle cell and epithelioid cell nevi with atypia and metastasis (malignant Spitz nevus). Am J Surg Pathol. 1989;13:931-939.
- Barnhill RL. Childhood melanoma. Semin Diagn Pathol. 1998;15:189-194.
- Melnik MK, Urdaneta LF, Al-Jurf AS, et al. Malignant melanoma in childhood and adolescence. Am Surg. 1986;52:142-147.
- Shapiro PE. Spitz nevi. J Am Acad Dermatol. 1993;29:667-668.
- Gurbuz Y, Apaydin R, Muezzinoglu B, et al. A current dilemma in histopathology: atypical spitz tumor or Spitzoid melanoma? Pediatr Dermatol. 2002;19:99-102.
- Lohmann CM, Coit DG, Brady MS, et al. Sentinel lymph node biopsy in patients with diagnostically controversial spitzoid melanocytic tumors. Am J Surg Pathol. 2002;26:47-55.
- Handfield-Jones SE, Smith NP. Malignant melanoma in childhood. Br J Dermatol. 1996;134:607-616.
- Crotty KA, McCarthy SW, Palmer AA, et al. Malignant melanoma in childhood: a clinicopathologic study of 13 cases and comparison with Spitz nevi. World J Surg. 1992;16:179-185.
- Lerman RI, Murray D, O'Hara JM, et al. Malignant melanoma of childhood. a clinicopathologic study and a report of 12 cases. Cancer. 1970;25:436-449.
- Farmer ER, Gonin R, Hanna MP. Discordance in the histopathologic diagnosis of melanoma and melano-cytic nevi between expert pathologists. Hum Pathol.1996;27:528-531.
- Shimek CM, Golitz LE. The golden anniversary of the Spitz nevus. Arch Dermatol. 1999;135:333-335.
- Bastian BC, Wesselmann U, Pinkel D, et al. Molecular cytogenetic analysis of Spitz nevi shows clear differences to melanoma. J Invest Dermatol.1999; 113:1065-1069.
- Bastian BC, LeBoit PE, Hamm H, et al. Chromo-somal gains and losses in primary cutaneous melanomas detected by comparative genomic hybridization. Cancer Res.1998;58:2170-2175.
- Bergman R, Malkin L, Sabo E, et al. MIB-1 mono-clonal antibody to determine proliferative activity of Ki-67 antigen as an adjunct to the histopathologic dif-ferential diagnosis of Spitz nevi. J Am Acad Dermatol. 2001; 44:500-504.
- Li LX, Crotty KA, McCarthy SW, et al. A zonal com-parison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions. Am J Dermatopathol. 2000;22:489-495.
- McNutt NS, Urmacher C, Hakimian J, et al. Nevoid malignant melanoma: morphologicpatterns and immu-nohistochemical reactivity. J Cutan Pathol.1995;22:502-517.
- Kanter-Lewensohn L, Hedblad MA, Wejde J, et al. Immu-nohistochemical markers for distinguishing Spitz nevi from malignant melanomas. Mod Pathol.1997;10:917-920.
- Ribé A, McNutt NS. S100A6 protein expression is different in spitz nevi and melanomas. Mod Pathol.2003;16:505-511.
- Kaye VN, Dehner LP. Spindle and epithelioid cell nevus (Spitz nevus). natural history following biopsy. Arch Dermatol.1990;126:1581-1583.
- Omura EF, Kheir SM. Recurrent Spitz’s nevus. Am J. Dermatopathol.1984;6(suppl): 207212.
- Zaenglein AL, Heintz P, Kamino H, et al. Congenital Spitz nevus clinically mimicking melanoma. J Am Acad Dermatol.2002;47:441-444.
- Murphy ME, Boyer JD, Stashower ME, et al. The surgical management of Spitz nevi. Dermatol Surg. 2002;28:1065-1069.
- Zitelli JA, Brown C, Hanusa BH. Mohs micrographic surgery for the treatment of primary cutaneous melanoma. J Am Acad Dermatol. 1997;37:236-245.
- Kelley SW, Cockerell CJ. Sentinel lymph node biopsy as an adjunct to management of histologically difficult to diagnose melanocytic lesions: a proposal. J Am Acad Dermatol. 2000;42:527-530.
- Su LD, Fullen DR, Sondak VK, et al. Sentinel lymph node biopsy for patients with problematic spitzoid melanocytic lesions: a report on 18 patients. Cancer. 2003;97:499-507.
- Martinez JC, Otley CC. The management of melanoma and nonmelanoma skin cancer: a review for the primary care physician. Mayo Clin Proc. 2001;76:1253-1265.
What is the preferred treatment for a child with mild persistent asthma?
Low-dose inhaled corticosteroids are the preferred treatment for children with mild persistent asthma because they demonstrate superior reduction in severity and frequency of asthma exacerbations compared with alternatives (strength of recommendation [SOR]: A, based on multiple randomized controlled trials). As add-on therapy, nedocromil, theophylline, and cromolyn have all demonstrated a modest benefit in symptom control; leukotriene receptor antagonists are also recommended based on data from older children (SOR: B, cohort study). Unlike treatment of moderate or severe asthma, long-acting beta-agonists are not recommended (SOR: A, randomized trials).
Clear medication choices for mild asthma are supported by good evidence
John Heintzman, MD
Oregon Health and Science University, Portland
Physicians who routinely treat children with asthma are fortunate to have the body of evidence outlined in this review. Clear medication choices are supported in most instances by relatively clear comparisons with alternatives. In my practice, where many children can be classified in the “mild persistent” category, I am always surprised at how many patients’ families lack a clear understanding of the factors that trigger a child’s asthma and how to avoid them.
Another common clinical scenario among children and adolescents is exercise-induced asthma. Depending on the sport, the asthma can be classified as “mild persistent” or “mild intermittent.” for true intermittent symptoms, my clinical experience (and often parental preference) argues for pre-activity treatment with short acting beta-agonists as the most practical therapy.
Evidence summary
Mild persistent asthma is defined as forced expiratory volume over 1 second (FEV1) ≥80% predicted, with daytime symptoms more than twice per week but less than once daily, and nighttime symptoms more often than twice monthly.1
Low-dose inhaled corticosteroids
Two large randomized trials support using low-dose inhaled corticosteroids in these children. The Childhood Asthma Management Program (CAMP) study, which included 1041 children, evaluated treatment with either budesonide or nedocromil vs placebo. Patients taking budesonide had a lower rate of urgent care visits (absolute risk reduction [ARR]=10%; number needed to treat [NNT]=10; P=.02) compared with children taking nedocromil (ARR=6%; NNT=17; P=.02). The urgent care visits were reported as number of visits per 100 person-years.
In practical terms, this means that in order to decrease 1 urgent care visit, 1 patient would need to take budesonide for 10 years. However, because rates are not necessarily homogenous over time, the number of visits decreased during the first year may be different than the number of events decreased throughout the tenth year.
Children taking budesonide experienced 21.5% more episode-free days than those taking placebo (P=.01). No change was observed in the nedocromil group.2 In the inhaled Steroid Treatment As Regular Therapy (START) in early asthma study, budesonide demonstrated a 44% relative reduction in time to first severe asthma related event, compared with placebo (95% confidence interval [CI], 0.45–0.71; NNT=44; P=.0001).3
Theophylline
Theophylline is considered an alternative to inhaled corticosteroids. One study compared beclomethasone with theophylline in 195 children. This study found near-equivalent efficacy in doctor visits, hospitalizations, monthly peak expiratory flow rates, and FEV1; however, beclomethasone was superior to theophylline in maintaining symptom control and decreasing the use of inhaled bronchodilators and systemic steroids.
When compared with beclomethasone, theophylline was linked to 14% more central nervous system adverse effects (P<.001) and 17% more gastrointestinal disturbances (P<.001). Although beclomethasone induced more oral candidiasis compared with theophylline (8.9% vs 2.4%; P<.001), the incidence of this infection can be reduced by using a spacer.
Long-term systemic effects
The potential long-term adverse systemic effects of inhaled corticosteroids on growth, bone metabolism, and pituitary-adrenal function call for longer-term studies.4 A systematic review of 15 trials reported that the protective effect of leukotriene receptor antagonists is inferior to inhaled corticosteroids for adults (relative risk [RR]=1.71; 95% CI, 1.40–2.09); however, evidence is insufficient to extrapolate this to children.5
Beta-agonists
Evidence does not support use of long-acting beta-agonists as monotherapy or in combination with other medications for children with mild persistent asthma. Although 1 study showed an improvement in lung function for children taking budesonide plus formoterol compared with budesonide alone, the rate of severe exacerbations was lower for those taking budesonide alone (62% decrease vs 55.8% decrease; P=.001). Both groups had a 32% decrease in the number of rescue inhalations per day when compared with placebo (P=.0008).6
Recommendations from others
Recommendations are listed in the TABLE.1,7,8 Unlike the NAEPP and GINA asthma guidelines, the BTS/SIGN asthma guidelines define no objective measurement or staging classification to diagnose asthma among children. Diagnosis is determined by a child’s response to medication.8 Independent of any daily controller medication use, all children should have a short acting bronchodilator on hand in case of an acute attack.1,8
TABLE
Recommendations for treating mild persistent asthma
| GUIDELINE | DAILY CONTROLLER MEDICATION | ALTERNATIVE TREATMENT |
|---|---|---|
| National Asthma Education and Prevention Program (NAEPP)1 | Low-dose inhaled corticosteroids | Children <5: cromolyn, LTRAs Children >5: cromolyn, LTRAs, nedocromil, sustained release theophylline |
| Global initiative for asthma (GINA)7 | low-dose inhaled corticosteroids | All children: sustained released theophylline, Cromone, LTRAs |
| British Thoracic Society/Scottish intercollegiate Guidelines network (BTS/SIGN)8 | Inhaled steroids | All children: LTRAs, theophylline Children >5: cromones, nedocromil |
| LRTA leukotriene receptor antagonists. | ||
| Sources: NAEPP J Allergy Clin Immunol 20021; GINA Guidelines and Resources 20057 and BTS/SIGN, Thorax 2003.8 | ||
1. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics—2002. National Asthma Education and Prevention Program. J Allergy Clin Immunol 2002;110:S141-S219.
2. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med 2000;343:1054-1063.
3. Pauwels RA, Pedersen S, Busse WW, et al. START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-1076.
4. Reed CE, Offord KP, Nelson HS, Li JT, Tinkelman DG. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. J Allergy Clin Immunol 1998;101:14-23.
5. Ducharme FM, Salvio F, Ducharme F. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children (Cochrane review). In: The Cochrane Library. 2006 Issue 2. Chichester, UK: John Wiley and Sons, Ltd.
6. O’byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-1397.
7. The Global Initiative for Asthma. Guidelines and Resources: 2005 Update. Available at: www.ginasthma.com/Guidelineitem.asp??I1=2&I2=1&intId=60. Accessed January 9, 2007.
8. British Thoracic Society Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. A national clinical guideline. Thorax 2003;58:i1-i94.
Low-dose inhaled corticosteroids are the preferred treatment for children with mild persistent asthma because they demonstrate superior reduction in severity and frequency of asthma exacerbations compared with alternatives (strength of recommendation [SOR]: A, based on multiple randomized controlled trials). As add-on therapy, nedocromil, theophylline, and cromolyn have all demonstrated a modest benefit in symptom control; leukotriene receptor antagonists are also recommended based on data from older children (SOR: B, cohort study). Unlike treatment of moderate or severe asthma, long-acting beta-agonists are not recommended (SOR: A, randomized trials).
Clear medication choices for mild asthma are supported by good evidence
John Heintzman, MD
Oregon Health and Science University, Portland
Physicians who routinely treat children with asthma are fortunate to have the body of evidence outlined in this review. Clear medication choices are supported in most instances by relatively clear comparisons with alternatives. In my practice, where many children can be classified in the “mild persistent” category, I am always surprised at how many patients’ families lack a clear understanding of the factors that trigger a child’s asthma and how to avoid them.
Another common clinical scenario among children and adolescents is exercise-induced asthma. Depending on the sport, the asthma can be classified as “mild persistent” or “mild intermittent.” for true intermittent symptoms, my clinical experience (and often parental preference) argues for pre-activity treatment with short acting beta-agonists as the most practical therapy.
Evidence summary
Mild persistent asthma is defined as forced expiratory volume over 1 second (FEV1) ≥80% predicted, with daytime symptoms more than twice per week but less than once daily, and nighttime symptoms more often than twice monthly.1
Low-dose inhaled corticosteroids
Two large randomized trials support using low-dose inhaled corticosteroids in these children. The Childhood Asthma Management Program (CAMP) study, which included 1041 children, evaluated treatment with either budesonide or nedocromil vs placebo. Patients taking budesonide had a lower rate of urgent care visits (absolute risk reduction [ARR]=10%; number needed to treat [NNT]=10; P=.02) compared with children taking nedocromil (ARR=6%; NNT=17; P=.02). The urgent care visits were reported as number of visits per 100 person-years.
In practical terms, this means that in order to decrease 1 urgent care visit, 1 patient would need to take budesonide for 10 years. However, because rates are not necessarily homogenous over time, the number of visits decreased during the first year may be different than the number of events decreased throughout the tenth year.
Children taking budesonide experienced 21.5% more episode-free days than those taking placebo (P=.01). No change was observed in the nedocromil group.2 In the inhaled Steroid Treatment As Regular Therapy (START) in early asthma study, budesonide demonstrated a 44% relative reduction in time to first severe asthma related event, compared with placebo (95% confidence interval [CI], 0.45–0.71; NNT=44; P=.0001).3
Theophylline
Theophylline is considered an alternative to inhaled corticosteroids. One study compared beclomethasone with theophylline in 195 children. This study found near-equivalent efficacy in doctor visits, hospitalizations, monthly peak expiratory flow rates, and FEV1; however, beclomethasone was superior to theophylline in maintaining symptom control and decreasing the use of inhaled bronchodilators and systemic steroids.
When compared with beclomethasone, theophylline was linked to 14% more central nervous system adverse effects (P<.001) and 17% more gastrointestinal disturbances (P<.001). Although beclomethasone induced more oral candidiasis compared with theophylline (8.9% vs 2.4%; P<.001), the incidence of this infection can be reduced by using a spacer.
Long-term systemic effects
The potential long-term adverse systemic effects of inhaled corticosteroids on growth, bone metabolism, and pituitary-adrenal function call for longer-term studies.4 A systematic review of 15 trials reported that the protective effect of leukotriene receptor antagonists is inferior to inhaled corticosteroids for adults (relative risk [RR]=1.71; 95% CI, 1.40–2.09); however, evidence is insufficient to extrapolate this to children.5
Beta-agonists
Evidence does not support use of long-acting beta-agonists as monotherapy or in combination with other medications for children with mild persistent asthma. Although 1 study showed an improvement in lung function for children taking budesonide plus formoterol compared with budesonide alone, the rate of severe exacerbations was lower for those taking budesonide alone (62% decrease vs 55.8% decrease; P=.001). Both groups had a 32% decrease in the number of rescue inhalations per day when compared with placebo (P=.0008).6
Recommendations from others
Recommendations are listed in the TABLE.1,7,8 Unlike the NAEPP and GINA asthma guidelines, the BTS/SIGN asthma guidelines define no objective measurement or staging classification to diagnose asthma among children. Diagnosis is determined by a child’s response to medication.8 Independent of any daily controller medication use, all children should have a short acting bronchodilator on hand in case of an acute attack.1,8
TABLE
Recommendations for treating mild persistent asthma
| GUIDELINE | DAILY CONTROLLER MEDICATION | ALTERNATIVE TREATMENT |
|---|---|---|
| National Asthma Education and Prevention Program (NAEPP)1 | Low-dose inhaled corticosteroids | Children <5: cromolyn, LTRAs Children >5: cromolyn, LTRAs, nedocromil, sustained release theophylline |
| Global initiative for asthma (GINA)7 | low-dose inhaled corticosteroids | All children: sustained released theophylline, Cromone, LTRAs |
| British Thoracic Society/Scottish intercollegiate Guidelines network (BTS/SIGN)8 | Inhaled steroids | All children: LTRAs, theophylline Children >5: cromones, nedocromil |
| LRTA leukotriene receptor antagonists. | ||
| Sources: NAEPP J Allergy Clin Immunol 20021; GINA Guidelines and Resources 20057 and BTS/SIGN, Thorax 2003.8 | ||
Low-dose inhaled corticosteroids are the preferred treatment for children with mild persistent asthma because they demonstrate superior reduction in severity and frequency of asthma exacerbations compared with alternatives (strength of recommendation [SOR]: A, based on multiple randomized controlled trials). As add-on therapy, nedocromil, theophylline, and cromolyn have all demonstrated a modest benefit in symptom control; leukotriene receptor antagonists are also recommended based on data from older children (SOR: B, cohort study). Unlike treatment of moderate or severe asthma, long-acting beta-agonists are not recommended (SOR: A, randomized trials).
Clear medication choices for mild asthma are supported by good evidence
John Heintzman, MD
Oregon Health and Science University, Portland
Physicians who routinely treat children with asthma are fortunate to have the body of evidence outlined in this review. Clear medication choices are supported in most instances by relatively clear comparisons with alternatives. In my practice, where many children can be classified in the “mild persistent” category, I am always surprised at how many patients’ families lack a clear understanding of the factors that trigger a child’s asthma and how to avoid them.
Another common clinical scenario among children and adolescents is exercise-induced asthma. Depending on the sport, the asthma can be classified as “mild persistent” or “mild intermittent.” for true intermittent symptoms, my clinical experience (and often parental preference) argues for pre-activity treatment with short acting beta-agonists as the most practical therapy.
Evidence summary
Mild persistent asthma is defined as forced expiratory volume over 1 second (FEV1) ≥80% predicted, with daytime symptoms more than twice per week but less than once daily, and nighttime symptoms more often than twice monthly.1
Low-dose inhaled corticosteroids
Two large randomized trials support using low-dose inhaled corticosteroids in these children. The Childhood Asthma Management Program (CAMP) study, which included 1041 children, evaluated treatment with either budesonide or nedocromil vs placebo. Patients taking budesonide had a lower rate of urgent care visits (absolute risk reduction [ARR]=10%; number needed to treat [NNT]=10; P=.02) compared with children taking nedocromil (ARR=6%; NNT=17; P=.02). The urgent care visits were reported as number of visits per 100 person-years.
In practical terms, this means that in order to decrease 1 urgent care visit, 1 patient would need to take budesonide for 10 years. However, because rates are not necessarily homogenous over time, the number of visits decreased during the first year may be different than the number of events decreased throughout the tenth year.
Children taking budesonide experienced 21.5% more episode-free days than those taking placebo (P=.01). No change was observed in the nedocromil group.2 In the inhaled Steroid Treatment As Regular Therapy (START) in early asthma study, budesonide demonstrated a 44% relative reduction in time to first severe asthma related event, compared with placebo (95% confidence interval [CI], 0.45–0.71; NNT=44; P=.0001).3
Theophylline
Theophylline is considered an alternative to inhaled corticosteroids. One study compared beclomethasone with theophylline in 195 children. This study found near-equivalent efficacy in doctor visits, hospitalizations, monthly peak expiratory flow rates, and FEV1; however, beclomethasone was superior to theophylline in maintaining symptom control and decreasing the use of inhaled bronchodilators and systemic steroids.
When compared with beclomethasone, theophylline was linked to 14% more central nervous system adverse effects (P<.001) and 17% more gastrointestinal disturbances (P<.001). Although beclomethasone induced more oral candidiasis compared with theophylline (8.9% vs 2.4%; P<.001), the incidence of this infection can be reduced by using a spacer.
Long-term systemic effects
The potential long-term adverse systemic effects of inhaled corticosteroids on growth, bone metabolism, and pituitary-adrenal function call for longer-term studies.4 A systematic review of 15 trials reported that the protective effect of leukotriene receptor antagonists is inferior to inhaled corticosteroids for adults (relative risk [RR]=1.71; 95% CI, 1.40–2.09); however, evidence is insufficient to extrapolate this to children.5
Beta-agonists
Evidence does not support use of long-acting beta-agonists as monotherapy or in combination with other medications for children with mild persistent asthma. Although 1 study showed an improvement in lung function for children taking budesonide plus formoterol compared with budesonide alone, the rate of severe exacerbations was lower for those taking budesonide alone (62% decrease vs 55.8% decrease; P=.001). Both groups had a 32% decrease in the number of rescue inhalations per day when compared with placebo (P=.0008).6
Recommendations from others
Recommendations are listed in the TABLE.1,7,8 Unlike the NAEPP and GINA asthma guidelines, the BTS/SIGN asthma guidelines define no objective measurement or staging classification to diagnose asthma among children. Diagnosis is determined by a child’s response to medication.8 Independent of any daily controller medication use, all children should have a short acting bronchodilator on hand in case of an acute attack.1,8
TABLE
Recommendations for treating mild persistent asthma
| GUIDELINE | DAILY CONTROLLER MEDICATION | ALTERNATIVE TREATMENT |
|---|---|---|
| National Asthma Education and Prevention Program (NAEPP)1 | Low-dose inhaled corticosteroids | Children <5: cromolyn, LTRAs Children >5: cromolyn, LTRAs, nedocromil, sustained release theophylline |
| Global initiative for asthma (GINA)7 | low-dose inhaled corticosteroids | All children: sustained released theophylline, Cromone, LTRAs |
| British Thoracic Society/Scottish intercollegiate Guidelines network (BTS/SIGN)8 | Inhaled steroids | All children: LTRAs, theophylline Children >5: cromones, nedocromil |
| LRTA leukotriene receptor antagonists. | ||
| Sources: NAEPP J Allergy Clin Immunol 20021; GINA Guidelines and Resources 20057 and BTS/SIGN, Thorax 2003.8 | ||
1. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics—2002. National Asthma Education and Prevention Program. J Allergy Clin Immunol 2002;110:S141-S219.
2. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med 2000;343:1054-1063.
3. Pauwels RA, Pedersen S, Busse WW, et al. START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-1076.
4. Reed CE, Offord KP, Nelson HS, Li JT, Tinkelman DG. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. J Allergy Clin Immunol 1998;101:14-23.
5. Ducharme FM, Salvio F, Ducharme F. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children (Cochrane review). In: The Cochrane Library. 2006 Issue 2. Chichester, UK: John Wiley and Sons, Ltd.
6. O’byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-1397.
7. The Global Initiative for Asthma. Guidelines and Resources: 2005 Update. Available at: www.ginasthma.com/Guidelineitem.asp??I1=2&I2=1&intId=60. Accessed January 9, 2007.
8. British Thoracic Society Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. A national clinical guideline. Thorax 2003;58:i1-i94.
1. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics—2002. National Asthma Education and Prevention Program. J Allergy Clin Immunol 2002;110:S141-S219.
2. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med 2000;343:1054-1063.
3. Pauwels RA, Pedersen S, Busse WW, et al. START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-1076.
4. Reed CE, Offord KP, Nelson HS, Li JT, Tinkelman DG. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. J Allergy Clin Immunol 1998;101:14-23.
5. Ducharme FM, Salvio F, Ducharme F. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children (Cochrane review). In: The Cochrane Library. 2006 Issue 2. Chichester, UK: John Wiley and Sons, Ltd.
6. O’byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-1397.
7. The Global Initiative for Asthma. Guidelines and Resources: 2005 Update. Available at: www.ginasthma.com/Guidelineitem.asp??I1=2&I2=1&intId=60. Accessed January 9, 2007.
8. British Thoracic Society Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. A national clinical guideline. Thorax 2003;58:i1-i94.
Evidence-based answers from the Family Physicians Inquiries Network
Avoid confusion over terms when billing McCall culdoplasty ... Complete and transvaginal US scan must be specified
Your code choices are:
58263 Vaginal hysterectomy, for uterus 250 g or less; with removal of tube(s), and/or ovary(s), with repair of enterocele
58270 Vaginal hysterectomy, for uterus 250 g or less; with repair of enterocele
58292 Vaginal hysterectomy, for uterus greater than 250 g; with removal of tube(s) and/or ovary(s), with repair of enterocele
58294 Vaginal hysterectomy, for uterus greater than 250 g; with repair of enterocele
Don’t blame your billing staff if this is what occurred. The term “McCall culdoplasty” appears nowhere in the CPT book, so your billers would need to know that you actually performed an enterocele repair.
Correctly communicating what you did is an important step in getting the claim paid in a timely manner. Refile with the correct code!
Read a description of the technique of McCall culdoplasty.
Complete and transvaginal US scan must be specified
Your code choices are:
58263 Vaginal hysterectomy, for uterus 250 g or less; with removal of tube(s), and/or ovary(s), with repair of enterocele
58270 Vaginal hysterectomy, for uterus 250 g or less; with repair of enterocele
58292 Vaginal hysterectomy, for uterus greater than 250 g; with removal of tube(s) and/or ovary(s), with repair of enterocele
58294 Vaginal hysterectomy, for uterus greater than 250 g; with repair of enterocele
Don’t blame your billing staff if this is what occurred. The term “McCall culdoplasty” appears nowhere in the CPT book, so your billers would need to know that you actually performed an enterocele repair.
Correctly communicating what you did is an important step in getting the claim paid in a timely manner. Refile with the correct code!
Read a description of the technique of McCall culdoplasty.
Complete and transvaginal US scan must be specified
Your code choices are:
58263 Vaginal hysterectomy, for uterus 250 g or less; with removal of tube(s), and/or ovary(s), with repair of enterocele
58270 Vaginal hysterectomy, for uterus 250 g or less; with repair of enterocele
58292 Vaginal hysterectomy, for uterus greater than 250 g; with removal of tube(s) and/or ovary(s), with repair of enterocele
58294 Vaginal hysterectomy, for uterus greater than 250 g; with repair of enterocele
Don’t blame your billing staff if this is what occurred. The term “McCall culdoplasty” appears nowhere in the CPT book, so your billers would need to know that you actually performed an enterocele repair.
Correctly communicating what you did is an important step in getting the claim paid in a timely manner. Refile with the correct code!
Read a description of the technique of McCall culdoplasty.
Complete and transvaginal US scan must be specified
Limits of care: What events can you prevent?
Psychotic patient declines hospital admission, drives into an office building
Cook County (IL) Circuit Court
The patient, age 43, had been treated for mental illness for many years. He was voluntarily admitted to a hospital under the care of his psychiatrist, and was discharged at his own request a few days later. He had improved and was not considered a candidate for involuntary admission because he was not a danger to himself or others.
The patient then informed the psychiatrist that he did not want to continue treatment and said he had an appointment with a new psychiatrist within 2 weeks.
Five days later, the patient went to another hospital for voluntary admission. He was seen by an emergency room physician, who determined the patient was a candidate for voluntary admission. The patient, however, decided to leave the hospital while a bed was being arranged.
Two days later, the patient began having auditory and visual hallucinations. He then drove his car through the glass doors of an office building. No one was injured, but the patient was arrested and convicted of felony damage to property.
In his suit, the patient alleged his longtime psychiatrist was negligent and failed to properly treat him to avoid development of hallucinations. The psychiatrist argued that involuntary admission was not indicated and that the care given was appropriate.
- A defense verdict was returned
Patient commits suicide after discharge
Cook County (IL) Circuit Court
A patient, age 45, committed suicide by taking lethal doses of medication prescribed by her psychiatrist. The patient had suffered from severe depression, personality disorder, and substance abuse. The day before her death, she went to a hospital emergency room, where she was assessed for suicide and released without the psychiatrist having been notified.
The patient’s family claimed that the psychiatrist was negligent because he did not adequately assess or monitor the patient’s clinical condition at sufficient intervals over the 3 months preceding her suicide. The family also alleged that the psychiatrist prescribed oxycodone inappropriately.
The psychiatrist argued that proper care was given and that the patient failed to provide a complete, accurate medical history at the emergency room visit and did not to consent to admission.
- A defense verdict was returned
Could admission have prevented patient’s suicide?
Douglas County (NE) District Court
A patient in his mid-60s with a history of depression committed suicide with a gunshot wound to the head. Before his suicide, the patient was seeing a psychiatrist and psychologist for depression and emotional problems.
The patient’s family alleged the psychiatrist failed to diagnose the severity of the patient’s problems and admit him to a hospital for treatment and observation. The psychiatrist and psychologist denied negligence.
- A defense verdict was returned
Medical malpractice law is constantly evolving to determine what constitutes “negligent care.” The legal standard requires a patient who brings a negligence claim against a psychiatrist to prove:
- a relationship between patient and psychiatrist such that a duty of care exists
- the duty was breached—meaning the standard of care was not met
- the breach of duty caused the injury.
Relationship rules
The first case highlights issues surrounding the patient-psychiatrist relationship. In general, once you have agreed to treat a patient, a doctor-patient relationship and duty of care exists.
In the first case, the patient informed his longtime psychiatrist that he no longer wanted to continue care after discharge. A psychiatrist who terminates a doctor-patient relationship should provide written notice, an explanation of termination, and referrals and continue to care for the patient for a reasonable period.1 No such duty exists, however, when the patient ends treatment. Courts have found that the patient has not been abandoned when he or she voluntarily and unilaterally terminates the relationship.2,3
The relationship ends the moment the patient terminates care, unless the patient is not competent to make that unilateral decision. In that situation, your duty of care to the patient continues.2 When a competent patient terminates care, document the date and time of termination and the patient’s competence.
When relationships begin
The patient in the first case had an appointment with a new psychiatrist within 2 weeks. Is the new psychiatrist liable for what happens in the intervening period or does the relationship begin when the patient has been examined or treated? The legal question of when a physician-patient relationship is created remains problematic. Standards vary from state to state, but general principles offer some guidance.
The physician-patient relationship is a contract. The court would examine parties’ actions to ascertain their intent to determine if the patient reasonably believed that the physician—by actions or words—agreed to provide necessary medical care. Additionally, whether a relationship exists depends on the specific facts and circumstances of each situation.
There is some authority, across many jurisdictions, that a physician-patient relationship is established only when a physician conducts the initial history and physical examination. In some cases, however, the relationship has been found to exist at an earlier point, such as when a physician gave a referred patient an appointment for a consultation. When in doubt, assume the relationship exists.4
Duty of care
These cases raise areas where possible duty of care was breached:
- negligent prescription of medication
- failure to assess suicidal thinking.
Assessing suicide risk. Negligence in the second and third cases is based upon failure to assess suicidal thoughts. The legal system recognizes that psychiatrists cannot predict suicide,6 and mistakes in clinical judgment are not the same as negligence. Psychiatrists, however, are required to assess suicide risk and intervene appropriately.
When defending a negligence claim, the profession’s custom—reflected by the standard of care common to others with the practitioner’s training—is the benchmark against which the courts measure negligence. Therefore, take steps determined appropriate by the profession and document this risk assessment.7 For example, ask the patient about:
- suicidal thoughts and intent
- stressors
- history of suicidal behavior/attempts
- substance use
- signs and symptoms of depression
- bipolar disorder
- psychosis.8
Prescriptions. No clear line defines negligence when potentially dangerous medications are prescribed to a suicidal patient. Some psychiatrists dispense limited quantities of medications and see the patient weekly to monitor mood and medication. But even then a psychiatrist cannot prevent suicide—for example, the patient may have multiple prescribers or hoard medications. The concept of “sufficient intervals” to see a patient is determined case-by-case.
Documentation. Make suicide assessments an ongoing process. Document all aspects of the patient’s care, stability, and suicide risk, and reasons for the visit intervals. Indicate in the records your risk-benefit assessment in making treatment decisions.
Cases are selected byfrom Medical Malpractice Verdicts, Settlements & Experts, with permission of its editor, Lewis Laska of Nashville, TN (www.verdictslaska.com). Information may be incomplete in some instances, but these cases represent clinical situations that typically result in litigation.
Drug brand name
- Oxycodone • Percocet
1. American Medical Association Code of Medical Ethics, Opinion 8.115.
2. Knapp v. Eppright, 783 SW2d 293 (Tex 1989).
3. Saunders v. Tisher (Maine Sup. Jud. Ct. 2006).
4. Physicians Risk Management Update. The physician-patient relationship: when does it begin? Available at: http://www.phyins.com/pi/risk/updates/mayjun04.html. Accessed December 28, 2006.
5. American Psychiatric Association. Principles of medical ethics with annotations especially applicable to psychiatry. Washington, DC; 2006. Available at: http://www.psych.org/psych_pract/ethics/ppaethics.cfm. Accessed December 28, 2006.
6. Pokorny A. Prediction of suicide in psychiatric patients. Report of a prospective study. Arch Gen Psychiatry 1983;40(3):249-57.
7. Packman WL, Pennuto TO, Bongar B, Orthwein J. Legal issues of professional negligence in suicide cases. Behav Sci Law 2004;22:697-713.
8. Simon RI. The suicidal patient. In: Lifson LE, Simon RI, eds. The mental health practitioner and the law: a comprehensive handbook. Cambridge, MA: Harvard University Press; 1998:166-86.
9. Maunz v. Perales, 276 Kan. 313, 76 P.3d 1027 (Kan 2003).
Psychotic patient declines hospital admission, drives into an office building
Cook County (IL) Circuit Court
The patient, age 43, had been treated for mental illness for many years. He was voluntarily admitted to a hospital under the care of his psychiatrist, and was discharged at his own request a few days later. He had improved and was not considered a candidate for involuntary admission because he was not a danger to himself or others.
The patient then informed the psychiatrist that he did not want to continue treatment and said he had an appointment with a new psychiatrist within 2 weeks.
Five days later, the patient went to another hospital for voluntary admission. He was seen by an emergency room physician, who determined the patient was a candidate for voluntary admission. The patient, however, decided to leave the hospital while a bed was being arranged.
Two days later, the patient began having auditory and visual hallucinations. He then drove his car through the glass doors of an office building. No one was injured, but the patient was arrested and convicted of felony damage to property.
In his suit, the patient alleged his longtime psychiatrist was negligent and failed to properly treat him to avoid development of hallucinations. The psychiatrist argued that involuntary admission was not indicated and that the care given was appropriate.
- A defense verdict was returned
Patient commits suicide after discharge
Cook County (IL) Circuit Court
A patient, age 45, committed suicide by taking lethal doses of medication prescribed by her psychiatrist. The patient had suffered from severe depression, personality disorder, and substance abuse. The day before her death, she went to a hospital emergency room, where she was assessed for suicide and released without the psychiatrist having been notified.
The patient’s family claimed that the psychiatrist was negligent because he did not adequately assess or monitor the patient’s clinical condition at sufficient intervals over the 3 months preceding her suicide. The family also alleged that the psychiatrist prescribed oxycodone inappropriately.
The psychiatrist argued that proper care was given and that the patient failed to provide a complete, accurate medical history at the emergency room visit and did not to consent to admission.
- A defense verdict was returned
Could admission have prevented patient’s suicide?
Douglas County (NE) District Court
A patient in his mid-60s with a history of depression committed suicide with a gunshot wound to the head. Before his suicide, the patient was seeing a psychiatrist and psychologist for depression and emotional problems.
The patient’s family alleged the psychiatrist failed to diagnose the severity of the patient’s problems and admit him to a hospital for treatment and observation. The psychiatrist and psychologist denied negligence.
- A defense verdict was returned
Medical malpractice law is constantly evolving to determine what constitutes “negligent care.” The legal standard requires a patient who brings a negligence claim against a psychiatrist to prove:
- a relationship between patient and psychiatrist such that a duty of care exists
- the duty was breached—meaning the standard of care was not met
- the breach of duty caused the injury.
Relationship rules
The first case highlights issues surrounding the patient-psychiatrist relationship. In general, once you have agreed to treat a patient, a doctor-patient relationship and duty of care exists.
In the first case, the patient informed his longtime psychiatrist that he no longer wanted to continue care after discharge. A psychiatrist who terminates a doctor-patient relationship should provide written notice, an explanation of termination, and referrals and continue to care for the patient for a reasonable period.1 No such duty exists, however, when the patient ends treatment. Courts have found that the patient has not been abandoned when he or she voluntarily and unilaterally terminates the relationship.2,3
The relationship ends the moment the patient terminates care, unless the patient is not competent to make that unilateral decision. In that situation, your duty of care to the patient continues.2 When a competent patient terminates care, document the date and time of termination and the patient’s competence.
When relationships begin
The patient in the first case had an appointment with a new psychiatrist within 2 weeks. Is the new psychiatrist liable for what happens in the intervening period or does the relationship begin when the patient has been examined or treated? The legal question of when a physician-patient relationship is created remains problematic. Standards vary from state to state, but general principles offer some guidance.
The physician-patient relationship is a contract. The court would examine parties’ actions to ascertain their intent to determine if the patient reasonably believed that the physician—by actions or words—agreed to provide necessary medical care. Additionally, whether a relationship exists depends on the specific facts and circumstances of each situation.
There is some authority, across many jurisdictions, that a physician-patient relationship is established only when a physician conducts the initial history and physical examination. In some cases, however, the relationship has been found to exist at an earlier point, such as when a physician gave a referred patient an appointment for a consultation. When in doubt, assume the relationship exists.4
Duty of care
These cases raise areas where possible duty of care was breached:
- negligent prescription of medication
- failure to assess suicidal thinking.
Assessing suicide risk. Negligence in the second and third cases is based upon failure to assess suicidal thoughts. The legal system recognizes that psychiatrists cannot predict suicide,6 and mistakes in clinical judgment are not the same as negligence. Psychiatrists, however, are required to assess suicide risk and intervene appropriately.
When defending a negligence claim, the profession’s custom—reflected by the standard of care common to others with the practitioner’s training—is the benchmark against which the courts measure negligence. Therefore, take steps determined appropriate by the profession and document this risk assessment.7 For example, ask the patient about:
- suicidal thoughts and intent
- stressors
- history of suicidal behavior/attempts
- substance use
- signs and symptoms of depression
- bipolar disorder
- psychosis.8
Prescriptions. No clear line defines negligence when potentially dangerous medications are prescribed to a suicidal patient. Some psychiatrists dispense limited quantities of medications and see the patient weekly to monitor mood and medication. But even then a psychiatrist cannot prevent suicide—for example, the patient may have multiple prescribers or hoard medications. The concept of “sufficient intervals” to see a patient is determined case-by-case.
Documentation. Make suicide assessments an ongoing process. Document all aspects of the patient’s care, stability, and suicide risk, and reasons for the visit intervals. Indicate in the records your risk-benefit assessment in making treatment decisions.
Cases are selected byfrom Medical Malpractice Verdicts, Settlements & Experts, with permission of its editor, Lewis Laska of Nashville, TN (www.verdictslaska.com). Information may be incomplete in some instances, but these cases represent clinical situations that typically result in litigation.
Drug brand name
- Oxycodone • Percocet
Psychotic patient declines hospital admission, drives into an office building
Cook County (IL) Circuit Court
The patient, age 43, had been treated for mental illness for many years. He was voluntarily admitted to a hospital under the care of his psychiatrist, and was discharged at his own request a few days later. He had improved and was not considered a candidate for involuntary admission because he was not a danger to himself or others.
The patient then informed the psychiatrist that he did not want to continue treatment and said he had an appointment with a new psychiatrist within 2 weeks.
Five days later, the patient went to another hospital for voluntary admission. He was seen by an emergency room physician, who determined the patient was a candidate for voluntary admission. The patient, however, decided to leave the hospital while a bed was being arranged.
Two days later, the patient began having auditory and visual hallucinations. He then drove his car through the glass doors of an office building. No one was injured, but the patient was arrested and convicted of felony damage to property.
In his suit, the patient alleged his longtime psychiatrist was negligent and failed to properly treat him to avoid development of hallucinations. The psychiatrist argued that involuntary admission was not indicated and that the care given was appropriate.
- A defense verdict was returned
Patient commits suicide after discharge
Cook County (IL) Circuit Court
A patient, age 45, committed suicide by taking lethal doses of medication prescribed by her psychiatrist. The patient had suffered from severe depression, personality disorder, and substance abuse. The day before her death, she went to a hospital emergency room, where she was assessed for suicide and released without the psychiatrist having been notified.
The patient’s family claimed that the psychiatrist was negligent because he did not adequately assess or monitor the patient’s clinical condition at sufficient intervals over the 3 months preceding her suicide. The family also alleged that the psychiatrist prescribed oxycodone inappropriately.
The psychiatrist argued that proper care was given and that the patient failed to provide a complete, accurate medical history at the emergency room visit and did not to consent to admission.
- A defense verdict was returned
Could admission have prevented patient’s suicide?
Douglas County (NE) District Court
A patient in his mid-60s with a history of depression committed suicide with a gunshot wound to the head. Before his suicide, the patient was seeing a psychiatrist and psychologist for depression and emotional problems.
The patient’s family alleged the psychiatrist failed to diagnose the severity of the patient’s problems and admit him to a hospital for treatment and observation. The psychiatrist and psychologist denied negligence.
- A defense verdict was returned
Medical malpractice law is constantly evolving to determine what constitutes “negligent care.” The legal standard requires a patient who brings a negligence claim against a psychiatrist to prove:
- a relationship between patient and psychiatrist such that a duty of care exists
- the duty was breached—meaning the standard of care was not met
- the breach of duty caused the injury.
Relationship rules
The first case highlights issues surrounding the patient-psychiatrist relationship. In general, once you have agreed to treat a patient, a doctor-patient relationship and duty of care exists.
In the first case, the patient informed his longtime psychiatrist that he no longer wanted to continue care after discharge. A psychiatrist who terminates a doctor-patient relationship should provide written notice, an explanation of termination, and referrals and continue to care for the patient for a reasonable period.1 No such duty exists, however, when the patient ends treatment. Courts have found that the patient has not been abandoned when he or she voluntarily and unilaterally terminates the relationship.2,3
The relationship ends the moment the patient terminates care, unless the patient is not competent to make that unilateral decision. In that situation, your duty of care to the patient continues.2 When a competent patient terminates care, document the date and time of termination and the patient’s competence.
When relationships begin
The patient in the first case had an appointment with a new psychiatrist within 2 weeks. Is the new psychiatrist liable for what happens in the intervening period or does the relationship begin when the patient has been examined or treated? The legal question of when a physician-patient relationship is created remains problematic. Standards vary from state to state, but general principles offer some guidance.
The physician-patient relationship is a contract. The court would examine parties’ actions to ascertain their intent to determine if the patient reasonably believed that the physician—by actions or words—agreed to provide necessary medical care. Additionally, whether a relationship exists depends on the specific facts and circumstances of each situation.
There is some authority, across many jurisdictions, that a physician-patient relationship is established only when a physician conducts the initial history and physical examination. In some cases, however, the relationship has been found to exist at an earlier point, such as when a physician gave a referred patient an appointment for a consultation. When in doubt, assume the relationship exists.4
Duty of care
These cases raise areas where possible duty of care was breached:
- negligent prescription of medication
- failure to assess suicidal thinking.
Assessing suicide risk. Negligence in the second and third cases is based upon failure to assess suicidal thoughts. The legal system recognizes that psychiatrists cannot predict suicide,6 and mistakes in clinical judgment are not the same as negligence. Psychiatrists, however, are required to assess suicide risk and intervene appropriately.
When defending a negligence claim, the profession’s custom—reflected by the standard of care common to others with the practitioner’s training—is the benchmark against which the courts measure negligence. Therefore, take steps determined appropriate by the profession and document this risk assessment.7 For example, ask the patient about:
- suicidal thoughts and intent
- stressors
- history of suicidal behavior/attempts
- substance use
- signs and symptoms of depression
- bipolar disorder
- psychosis.8
Prescriptions. No clear line defines negligence when potentially dangerous medications are prescribed to a suicidal patient. Some psychiatrists dispense limited quantities of medications and see the patient weekly to monitor mood and medication. But even then a psychiatrist cannot prevent suicide—for example, the patient may have multiple prescribers or hoard medications. The concept of “sufficient intervals” to see a patient is determined case-by-case.
Documentation. Make suicide assessments an ongoing process. Document all aspects of the patient’s care, stability, and suicide risk, and reasons for the visit intervals. Indicate in the records your risk-benefit assessment in making treatment decisions.
Cases are selected byfrom Medical Malpractice Verdicts, Settlements & Experts, with permission of its editor, Lewis Laska of Nashville, TN (www.verdictslaska.com). Information may be incomplete in some instances, but these cases represent clinical situations that typically result in litigation.
Drug brand name
- Oxycodone • Percocet
1. American Medical Association Code of Medical Ethics, Opinion 8.115.
2. Knapp v. Eppright, 783 SW2d 293 (Tex 1989).
3. Saunders v. Tisher (Maine Sup. Jud. Ct. 2006).
4. Physicians Risk Management Update. The physician-patient relationship: when does it begin? Available at: http://www.phyins.com/pi/risk/updates/mayjun04.html. Accessed December 28, 2006.
5. American Psychiatric Association. Principles of medical ethics with annotations especially applicable to psychiatry. Washington, DC; 2006. Available at: http://www.psych.org/psych_pract/ethics/ppaethics.cfm. Accessed December 28, 2006.
6. Pokorny A. Prediction of suicide in psychiatric patients. Report of a prospective study. Arch Gen Psychiatry 1983;40(3):249-57.
7. Packman WL, Pennuto TO, Bongar B, Orthwein J. Legal issues of professional negligence in suicide cases. Behav Sci Law 2004;22:697-713.
8. Simon RI. The suicidal patient. In: Lifson LE, Simon RI, eds. The mental health practitioner and the law: a comprehensive handbook. Cambridge, MA: Harvard University Press; 1998:166-86.
9. Maunz v. Perales, 276 Kan. 313, 76 P.3d 1027 (Kan 2003).
1. American Medical Association Code of Medical Ethics, Opinion 8.115.
2. Knapp v. Eppright, 783 SW2d 293 (Tex 1989).
3. Saunders v. Tisher (Maine Sup. Jud. Ct. 2006).
4. Physicians Risk Management Update. The physician-patient relationship: when does it begin? Available at: http://www.phyins.com/pi/risk/updates/mayjun04.html. Accessed December 28, 2006.
5. American Psychiatric Association. Principles of medical ethics with annotations especially applicable to psychiatry. Washington, DC; 2006. Available at: http://www.psych.org/psych_pract/ethics/ppaethics.cfm. Accessed December 28, 2006.
6. Pokorny A. Prediction of suicide in psychiatric patients. Report of a prospective study. Arch Gen Psychiatry 1983;40(3):249-57.
7. Packman WL, Pennuto TO, Bongar B, Orthwein J. Legal issues of professional negligence in suicide cases. Behav Sci Law 2004;22:697-713.
8. Simon RI. The suicidal patient. In: Lifson LE, Simon RI, eds. The mental health practitioner and the law: a comprehensive handbook. Cambridge, MA: Harvard University Press; 1998:166-86.
9. Maunz v. Perales, 276 Kan. 313, 76 P.3d 1027 (Kan 2003).
Clarification
The method for skin grafting surgical defects of the nasal alar region known as the drumhead graft was invented and developed by Dr. J. Michael Wentzell of Billings, Mont. ('Drumhead' Technique May Spare Alar Graft Depressions, SKIN & ALLERGY NEWS, January 2007, p. 32). Dr. Bradley K. Draper of Billings presented Dr. Wentzell's technique at the annual meeting of the American Society for Dermatologic Surgery.
The method for skin grafting surgical defects of the nasal alar region known as the drumhead graft was invented and developed by Dr. J. Michael Wentzell of Billings, Mont. ('Drumhead' Technique May Spare Alar Graft Depressions, SKIN & ALLERGY NEWS, January 2007, p. 32). Dr. Bradley K. Draper of Billings presented Dr. Wentzell's technique at the annual meeting of the American Society for Dermatologic Surgery.
The method for skin grafting surgical defects of the nasal alar region known as the drumhead graft was invented and developed by Dr. J. Michael Wentzell of Billings, Mont. ('Drumhead' Technique May Spare Alar Graft Depressions, SKIN & ALLERGY NEWS, January 2007, p. 32). Dr. Bradley K. Draper of Billings presented Dr. Wentzell's technique at the annual meeting of the American Society for Dermatologic Surgery.
Brief Report / Krinsley
The last 15 years have brought reports in the medical literature of exciting advances in describing the relationship between hyperglycemia and adverse outcomes in a variety of clinical contexts involving acutely ill patients.19 Hyperglycemia in hospitalized patients was long thought to be an adaptive mechanism and, at least in the intensive care setting, was rarely treated below threshold values of 225‐250 mg/dL. The pioneering work of Furnary et al. and the Portland Diabetic Project was the first to demonstrate that close monitoring and treatment of hyperglycemia in diabetic patients undergoing cardiovascular surgery decreased the occurrence of deep sternal wound infections, a dreaded postoperative complication.10 A second publication documented the steady decrease in mortality among these patients over the years as the group's glycemic target was steadily lowered.11 In the last several years the mortality rate of diabetic patients undergoing cardiovascular surgery has decreased so that it now approximates that of nondiabetics, eliminating the diabetic disadvantage. This work set the stage for the landmark Leuven study, performed at Catholic University in Belgium and published by Van den Berghe's group in 2001.12 This prospective, randomized, controlled study involving 1548 mechanically ventilated patients in a surgical intensive care unit, 63% of whom had undergone cardiovascular surgery, compared the outcomes of patients treated with continuous intravenous insulin to achieve euglycemia (80‐110 mg/dL) to those of a control group that received treatment only when glucose level exceeded 210 mg/dL. The outcomes including a 37% reduction in hospital mortality in the treated group and a 40%‐50% reduction in numerous morbid conditions, including the need for renal replacement therapy, prolonged mechanical ventilation, prolonged antibiotic use, and critical illness polyneuropathy, that spawned a paradigm shift in ICU medicine. A large before‐and‐after study performed in a mixed medical‐surgical ICU of a university‐affiliated community hospital confirmed the mortality benefits of glycemic management, using a more modest target of 80‐140 mg/dL.13 Finally, a prospective, randomized, controlled trial in a medical ICU population by the Leuven investigators reported improvement in several morbidities and a mortality advantage from intensive glycemic control, targeting 80‐100 mg/dL, among patients with ICU stays longer than 3 days.14 Consequently, intensive glycemic management of critically ill patients is rapidly becoming a worldwide standard of care, presenting an array of challenges to clinicians involved in the care of these patients. This article presents an overview of the issues surrounding promulgation of protocols implementing tight glycemic control (TGC).
Building Blocks for Implementation of a Successful TGC Protocol
Data management tools
According to Curtis et al., A successful quality project requires transparent and informative data reporting. In the absence of timely and informative data reporting, interest wanes and projects lose momentum. On the other hand, actionable and interpretable data empower the ICU team, affirm that quality improvement efforts are making a difference, and increase the chances for sustainability.15
It is impossible to build a successful TGC program without proper data management tools. Conceptually, there are 2 levels of data reporting. At a minimum, an ICU must develop methods to demonstrate the effect of the protocol on glycemic levels. Optimally, there should also be a mechanism to report clinical and even financial outcomes resulting from the work. Quite simply, without ready access to these types of data it is unlikely that ICU cliniciansnurses, dieticians, and physicianswill continue to do the hard work necessary to allow a TGC program to achieve sustained success.
Examples of glycemic reports
Figure 1 shows a simple and powerful graphic used in the Stamford Hospital ICUthe mean monthly glucose value. This simple calculation does not account for severity of illness or prevalence of underlying diabetes, but it is readily understood and easy to create. The run chart below demonstrates the ICU's success in first implementing a treatment threshold of 140 mg/dL and, later, a treatment threshold of 125 mg/dL.
Another tool used in the Stamford Hospital ICU is a histogram that shows the percentage of glucose values that fall within discrete increments. Figure 2 details the outcomes in 3 periods: pre‐TGC, glucose 140, and glucose 125. This type of display powerfully demonstrates how the TGC protocols resulted in a marked increase in euglycemic values and dramatically reduced marked hyperglycemia.
The ability to capture useful sorts of data like these requires the assistance of the hospital's information technology department to create a link from the laboratory database to a data repository that the ICU's glycemic champion can regularly access and that displays the data in graphic form. Purchasing a point‐of‐care data management application provides an alternative solution. These applications can provide detailed reports on a unit's glycemic control, such as those displayed in Figures 1 and 2; some also have the capacity to delineate data by unit, individual practitioner, and patient.
Outcome data
The facility of an ICU to report data on glycemic control in a timely manner fulfills the minimum data requirement for successful implementation of a TGC protocol. However, sustained success depends on the unit's capacity to report information on relevant outcomes. It is not enough for an ICU director to be able to tell the hospital administration that the mean glucose level has decreased, from 160 to 135 mg/dL, for example, 6 months after institution of such a labor‐intensive program. The more relevant information is whether this intervention has had an effect on severity‐adjusted mortality, length of stay, and important comorbid conditions such as ICU‐acquired infections.
With innumerable measures that an ICU nursing or medical director might want to track, how should the measures to use be chosen?
A data set for a beginner might include the following parameters: demographics, including age, sex, and, possibly, ethnicity; admission and discharge dates and times; length of stay (LOS), ideally measured in exact time rather than number of calendar days; diagnosis; and ICU and hospital survival. The ICU data manager must develop a system to validate each patient's final discharge status from the hospital; some patients survive the ICU stay but die before hospital discharge, which therefore affects the ICU's hospital mortality rate.
The intermediate level of outcome reporting might include 2 additional elements: severity scoring and detailed information about episodes of mechanical ventilation. The most widely used models for scoring the severity of illness of ICU patients include the Acute Physiology and Chronic Health Evaluation (APACHE), the Simplified Acute Physiology Score (SAPS), and the Mortality Prediction Model (MPM).1620 The APACHE II system is the most widely quoted in the medical literature but is based on a validation cohort more than 25 years old.16 The scoring algorithms for APACHE III and APACHE IV have been released on the Web; the most recent iteration, APACHE IV, was developed using data from more than 100,000 admissions to a variety of types of ICUs between January 1, 2002, and December 31, 2003, and also includes predictions for ICU LOS.18 Use of these tools allows the ICU clinician to benchmark the unit's performance against this large heterogeneous group of ICU patients treated using contemporary ICU practice patterns. Important features of mechanical ventilation episodes worth tracking include: time of start and finish of each episode (to calculate ventilator LOS); whether the patient had an unplanned extubation; the percentage of patients who required reintubation after planned extubation; tracheostomy rate; and the use of continuous intravenous sedatives or paralytics.
An advanced data outcome system would be linked to various hospital data silos, allowing capture of all laboratory, pharmacy, and radiology charges into the ICU database, allowing financial analysis of ICU performance. Another link would funnel all important laboratory results into the database. Additional types of useful data include: ultimate discharge status of the patient (eg, home, skilled nursing facility, rehabilitation facility, another acute care hospital); procedures done in the ICU; infections acquired in the ICU; and comorbidities based on ICD‐9 codes. Several examples of the output possible with the use of the advanced data outcome system developed for use in the Stamford Hospital ICU are reported later in this article.
Protocol‐driven collaborative culture
Successful implementation of TGC is most likely in an environment that embraces standardized care using evidence‐based best practices. All routine aspects of care in the Stamford Hospital ICU are protocol driven. Some examples include deep‐vein thrombosis prophylaxis, stress ulcer prophylaxis, ventilator weaning, ventilator sedation, enteral nutrition, and potassium, phosphate, and magnesium repletion. These protocols were all in place when discussions began in the ICU about how to create a TGC protocol. The nurses were comfortable using protocols, and there were no longer any counterproductive arguments about physician autonomy of treatment decisions centered on these basic care issues. These factors facilitated adoption of the TGC protocol. Finally, the strength of the relationship binding the nursing and medical leadership of the ICU was fundamental to the program's success. A complex initiative such as TGC mandates that these parties share the same vision for the ICU.
Overcoming resistance
Adoption of TGC by an ICU will undoubtedly encounter resistance from the staff. The factors responsible for this are very real. An understanding and patient attitude by the unit's leadership will greatly facilitate implementation. Factors that are the basis for this resistance in part include:
-
TGC represents a fundamental paradigm shift in ICU care. Until recently, hyperglycemia, even at levels as high as 200‐250 mg/dL, has until recently been tolerated and ignored, as it has been considered a normal adaptive response to acute and severe illness.
-
Doing TGC correctly is hard work. This work includes the logistics of monitoring, explaining to families and patients the reasons for frequent finger sticks or blood testing (But Grandma isn't even a diabetic), being aware of the potential for significant discomfort to the patient, and having to make treatment decisions in response to all the newly acquired data.
-
Fear of hypoglycemia. Nurses want to protect, and not hurt, their patients. Insulin therapy, especially when targeting euglycemia or near‐euglycemia, is potentially dangerous.
An effective educational program directed to the staff, including nurses, staff physicians, and pharmacists, will help surmount this resistance. The components of this educational program should include: the basis in the medical literature for instituting intensive programs to monitor and treat patient glycemic levels; a review of the insulin formulations (subcutaneous, intravenous, long acting, and short acting) with emphasis on the different pharmacokinetic implications underlying their use; and a detailed analysis of factors associated with hypoglycemia.21, 22
Specific Issues Regarding TGC Implementation
Setting the glycemic target
What is the correct glycemic target? Van den Berghe et al. used a treatment threshold of 110 mg/dL for both her surgical ICU and medical ICU studies. The Stamford Hospital ICU trial, with a mixed population of medical, surgical, and cardiac patients, targeted 140 mg/dL.13
A detailed review of a very large cohort of patients treated in the Stamford Hospital ICU suggests that patients who achieve low euglycemia have the best survival (see Fig. 3). This analysis used APACHE methodology to analyze expected and actual mortality in relation to each patient's mean glucose during the ICU stay. The APACHE III and IV mortality prediction models use age, presence or absence of a group of important comorbidities, admitting diagnosis to the ICU, length of time in the ICU before ICU admission, location of the patient prior to ICU admission, and the most abnormal values of a large group of physiological parameters during the first 24 hours of ICU admission to derive a discrete prediction of hospital mortality for that patient. A standardized mortality ratio (SMR) can be calculated by dividing the patients' actual hospital mortality rate by the mean of all the individual predictions of mortality (SMR = actual/predicted mortality). A value less than 1 suggests that the patients in the observed cohort had a lower mortality rate than that predicted by the model.
Patients who achieved euglycemia (<110 mg/dL) in the surgical ICU study of Van den Berghe et al. also had the lowest mortality rates as well as the lowest incidence of the various comorbidities measured compared to those with intermediate blood glucose levels (110‐150 mg/dL). Those with the worst glycemic control (blood glucose > 150 mg/dL) had the highest mortality rate and the highest incidence of various serious comorbid conditions.23
Although available data support a euglycemic target, is this unequivocally the correct target for an ICU beginning TGC implementation? Not necessarily. Targeting 110 mg/dL requires an intensity of treatment that may be intimidating to an ICU staff, especially one without experience managing protocols. Moreover, the lower the glycemic target, the greater the risk for iatrogenic hypoglycemia. An ICU considering implementation of a TGC protocol might consider staged adoption. The initial target might be as high as 175 mg/dL. As the clinicians gain experience using the protocol, including acquiring and reporting data, the treatment threshold could be lowered. The Stamford Hospital ICU staff, with more than 5 years of experience developing a model of standardized care using evidence‐based best‐practice patient care protocols, spent several months arguing about the glycemic target when TGC was first discussed following publication of the initial Van den Berghe study.12 The director of Critical Care wanted to replicate Van den Berghe's work and urged a target of 110 mg/dL. The nurses refused. A compromise was reached: a 140 mg/dL treatment threshold. This confirms an important lesson: the ICU team must choose an achievable goal. It is noteworthy that after 2 years of successful use of the glucose 140 protocol, the Stamford Hospital ICU nurses initiated a revision of the protocol, deciding they wanted to target 125 mg/dL. Figure 4 illustrates the glycemic and mortality results comparing the last 3 years before TGC with the glucose 140 and glucose 125 periods.
Choosing a protocol
After choosing a glycemic target, the ICU leadership must agree on a protocol to achieve the objective. TGC protocols can be broadly characterized as directive or nondirective.
The Stamford Hospital ICU TGC protocol is an example of a nondirective protocol.13 The nursing staff considers the document a starting point for therapy decisions. Many patients receive insulin dosing at variance with the guidelines established by the document. A nurse is empowered to make these treatment decisions. This is not dissimilar to the process ICU nurses use when titrating a vasopressor to achieve a targeted goal for mean arterial pressure. Nondirective protocols are most suitable for ICU staffs that have had considerable prior experience using nurse‐driven protocols in an environment that supports and accepts standardized care.
A number of directive protocols have been published in the literature.24 Their unifying feature is the goal of prescribing a specific insulin dose for each set of circumstances a nurse may encounter. The patient's previous glucose level and the rate of change in glucose level are considered, and the document typically details the choices for insulin dosing in several columns based on the patient's previously documented sensitivity to insulin. Although this sort of protocol can be helpful in providing explicit guidance with insulin dosing, its complexity may impede adoption.
Another option is the use of tools that have been developed to assist an ICU in initiating and promulgating TGC protocols, including software applications that automatically calculate insulin dosing. Finally, work has been initiated on the development of monitors that provide near‐continuous monitoring of glucose levels at bedside.25, 26 Adoption of such monitoring will facilitate the implementation of TGC protocols because of its impact on eliminating the workflow burdens of intensive glycemic monitoring as well as markedly diminishing the risk of hypoglycemia.
Hypoglycemia
In the Van den Berghe et al. surgical ICU study, severe hypoglycemia, defined as a glucose level less than 40 mg/dL, occurred at least once among 5.1% of the patients in the intensively treated group versus in 0.8% of the patients in the conventionally treated group.12 The hypoglycemia was described as transient, a result of the frequency of monitoring during the study, and was not associated with overt adverse consequences. The incidence of severe hypoglycemia (<40 mg/dL) was described differently in the Stamford Hospital trial: 0.35% of all the values obtained during the baseline period, compared to 0.34% of those obtained during the treatment period, again without any overt adverse consequences.13 Nevertheless, it is not known with certainty whether having even a single episode of severe hypoglycemia independently contributes to the risk of mortality.
Vreisendorp recently identified a group of predisposing factors for the development of severe hypoglycemia among ICU patients undergoing TGC.21 The most important include: a decrease in the administration of nutrition without a concomitant change in insulin dosing; diabetes mellitus; insulin treatment; sepsis; inotropic support; and renal failure. The Stamford Hospital ICU TGC protocol document now includes a black box warning highlighting renal failure (associated with decreased clearance of administered insulin), hepatic failure, and sepsis (associated with decreased hepatic gluconeogenesis) as major risk factors for severe hypoglycemia. Ongoing reinforcement is necessary to encourage the ICU staff recognize these risk factors for severe hypoglycemia and respond by adopting more conservative insulin dosing and instituting more frequent glucose monitoring.
Economic Benefits of TGC
Recently published data support the economic benefits of intensive glycemic management. Van den Berghe et al. quantified costs attributable to ICU days, mechanical ventilation, and use of antibiotics, vasopressors, intotropic agents, and transfusions in the 2 treatment groups in their surgical ICU study. The savings per patient in the intensively treated group totaled $2638; mean LOS was 6.6 days.27, 28 Data from the Stamford Hospital ICU trial was analyzed differently, with quantification of all laboratory, pharmacy, and diagnostic imaging costs, as well as costs associated with ICU days, mechanical ventilation and days in the hospital after ICU discharge.29 The savings per patient in the intensively treated group totaled $1560. Notably, this occurred in the context of a much shorter LOS than that seen in the Belgian trial; mean and median LOS were only 3.4 and 1.7 days, respectively.
CONCLUSIONS
Intensive glycemic management of critically ill patients is emerging as a standard of care, based on data demonstrating its effectiveness in reducing mortality, morbidity, and costs. Intensive care unit staffs need to make important choices about the type of protocol most suitable for use, the glycemic target, and the mechanisms for avoiding hypoglycemia. The implementation of appropriate data management tools in a protocol‐driven environment that supports standardization of care will facilitate adoption of TGC.
- .Hyperglycemia during critical illness.J Parenter Enteral Nutr.2006;30:254–258.
- ,,, et al.Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview.Lancet.2000;355:773–778.
- .Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus.DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group.BMJ.1997;314:1512–1515.
- ,,, et al.Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview.Stroke.2001;32:2426–2432.
- ,,, et al.Admission glucose level and clinical outcomes in the NINDS rt‐PA Stroke Trial.Neurology.2002;59:669–674.
- ,,, et al.Outcomes and perioperative hyperglycemia in patients with or without diabetes mellitus undergoing coronary artery bypass grafting.Ann Thorac Surg.2003;75:1392–1399.
- ,,.Admission hyperglycemia as a prognostic indicator in trauma.J Trauma.2003;55:33–38.
- ,,.Perioperative diabetic and hyperglycemic management issues.Crit Care Med.2004;32:S116–S125.
- .Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients.Mayo Clinic Proc.2003;78:1471–1478.
- ,,, et al.Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures.Ann Thorac Surg.1999;67:352–360.
- ,,, et al.Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting.J Thorac Cardiovasc Surg.2003;125:1007–1021.
- ,,, et al.Intensive insulin therapy in the critically ill patients.N Engl J Med.2001;345:1359–1367.
- .Effect of an intensive glucose management protocol on the mortality of critically ill adult patients.Mayo Clin Proc.2004;79:992–1000.
- ,,, et al.Intensive insulin therapy in the medical ICU.N Engl J Med.2006;354:449–461.
- ,,, et al.Intensive care unit quality improvement: A “how‐to” guide for the interdisciplinary team.Crit Care Med.2006;34:211–218.
- ,,, et al.APACHE II. A severity of disease classification system.Crit Care Med.1985;13:818–829.
- ,,, et al.The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults.Chest.1991;100:1619–1636.
- http://www.cerner.com/public/Cerner_3.asp?id=3562. Accessed December 12,2006.
- ,,, et al.SAPS II revisited.Int Care Med.2005;31:416–423.
- ,,, et al.Mortality probability models (MPM II) based on an international cohort of intensive care unit patients.JAMA.1993;270:2478–86.
- ,,, et al.Predisposing factors for hypoglycemia in the intensive care unit.Crit Care Med.2006;34:96–101.
- ,,, et al.Evaluation of short‐term outcomes of hypoglycemia in the intensive care unit.Crit Care Med.2006;34:2714–1218.
- ,,, et al.Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control.Crit Care Med.2003;31:359–366.
- http://www.glycemiccontrol.net/Published_Protocols.htm. Accessed December 12,2006.
- ,,, et al.Validation of the OptiScanner, a new continuous glucose monitor.Crit Care Med.2005;33:S265.
- ,,, et al.ICU validation of the OptiScanner, a continuous glucose monitoring device.Crit Care Med.2006;34:A67.
- ,,, et al.Analysis of healthcare resource utilization with intensive insulin therapy in critically ill patients.Crit Care Med.2006;34:612–616.
- .A simple intervention that saves lives and money.Crit Care Med.2006;34:896.
- ,.Cost analysis of intensive glycemic control in critically ill adult patients.Chest.2006;129:644–650.
The last 15 years have brought reports in the medical literature of exciting advances in describing the relationship between hyperglycemia and adverse outcomes in a variety of clinical contexts involving acutely ill patients.19 Hyperglycemia in hospitalized patients was long thought to be an adaptive mechanism and, at least in the intensive care setting, was rarely treated below threshold values of 225‐250 mg/dL. The pioneering work of Furnary et al. and the Portland Diabetic Project was the first to demonstrate that close monitoring and treatment of hyperglycemia in diabetic patients undergoing cardiovascular surgery decreased the occurrence of deep sternal wound infections, a dreaded postoperative complication.10 A second publication documented the steady decrease in mortality among these patients over the years as the group's glycemic target was steadily lowered.11 In the last several years the mortality rate of diabetic patients undergoing cardiovascular surgery has decreased so that it now approximates that of nondiabetics, eliminating the diabetic disadvantage. This work set the stage for the landmark Leuven study, performed at Catholic University in Belgium and published by Van den Berghe's group in 2001.12 This prospective, randomized, controlled study involving 1548 mechanically ventilated patients in a surgical intensive care unit, 63% of whom had undergone cardiovascular surgery, compared the outcomes of patients treated with continuous intravenous insulin to achieve euglycemia (80‐110 mg/dL) to those of a control group that received treatment only when glucose level exceeded 210 mg/dL. The outcomes including a 37% reduction in hospital mortality in the treated group and a 40%‐50% reduction in numerous morbid conditions, including the need for renal replacement therapy, prolonged mechanical ventilation, prolonged antibiotic use, and critical illness polyneuropathy, that spawned a paradigm shift in ICU medicine. A large before‐and‐after study performed in a mixed medical‐surgical ICU of a university‐affiliated community hospital confirmed the mortality benefits of glycemic management, using a more modest target of 80‐140 mg/dL.13 Finally, a prospective, randomized, controlled trial in a medical ICU population by the Leuven investigators reported improvement in several morbidities and a mortality advantage from intensive glycemic control, targeting 80‐100 mg/dL, among patients with ICU stays longer than 3 days.14 Consequently, intensive glycemic management of critically ill patients is rapidly becoming a worldwide standard of care, presenting an array of challenges to clinicians involved in the care of these patients. This article presents an overview of the issues surrounding promulgation of protocols implementing tight glycemic control (TGC).
Building Blocks for Implementation of a Successful TGC Protocol
Data management tools
According to Curtis et al., A successful quality project requires transparent and informative data reporting. In the absence of timely and informative data reporting, interest wanes and projects lose momentum. On the other hand, actionable and interpretable data empower the ICU team, affirm that quality improvement efforts are making a difference, and increase the chances for sustainability.15
It is impossible to build a successful TGC program without proper data management tools. Conceptually, there are 2 levels of data reporting. At a minimum, an ICU must develop methods to demonstrate the effect of the protocol on glycemic levels. Optimally, there should also be a mechanism to report clinical and even financial outcomes resulting from the work. Quite simply, without ready access to these types of data it is unlikely that ICU cliniciansnurses, dieticians, and physicianswill continue to do the hard work necessary to allow a TGC program to achieve sustained success.
Examples of glycemic reports
Figure 1 shows a simple and powerful graphic used in the Stamford Hospital ICUthe mean monthly glucose value. This simple calculation does not account for severity of illness or prevalence of underlying diabetes, but it is readily understood and easy to create. The run chart below demonstrates the ICU's success in first implementing a treatment threshold of 140 mg/dL and, later, a treatment threshold of 125 mg/dL.
Another tool used in the Stamford Hospital ICU is a histogram that shows the percentage of glucose values that fall within discrete increments. Figure 2 details the outcomes in 3 periods: pre‐TGC, glucose 140, and glucose 125. This type of display powerfully demonstrates how the TGC protocols resulted in a marked increase in euglycemic values and dramatically reduced marked hyperglycemia.
The ability to capture useful sorts of data like these requires the assistance of the hospital's information technology department to create a link from the laboratory database to a data repository that the ICU's glycemic champion can regularly access and that displays the data in graphic form. Purchasing a point‐of‐care data management application provides an alternative solution. These applications can provide detailed reports on a unit's glycemic control, such as those displayed in Figures 1 and 2; some also have the capacity to delineate data by unit, individual practitioner, and patient.
Outcome data
The facility of an ICU to report data on glycemic control in a timely manner fulfills the minimum data requirement for successful implementation of a TGC protocol. However, sustained success depends on the unit's capacity to report information on relevant outcomes. It is not enough for an ICU director to be able to tell the hospital administration that the mean glucose level has decreased, from 160 to 135 mg/dL, for example, 6 months after institution of such a labor‐intensive program. The more relevant information is whether this intervention has had an effect on severity‐adjusted mortality, length of stay, and important comorbid conditions such as ICU‐acquired infections.
With innumerable measures that an ICU nursing or medical director might want to track, how should the measures to use be chosen?
A data set for a beginner might include the following parameters: demographics, including age, sex, and, possibly, ethnicity; admission and discharge dates and times; length of stay (LOS), ideally measured in exact time rather than number of calendar days; diagnosis; and ICU and hospital survival. The ICU data manager must develop a system to validate each patient's final discharge status from the hospital; some patients survive the ICU stay but die before hospital discharge, which therefore affects the ICU's hospital mortality rate.
The intermediate level of outcome reporting might include 2 additional elements: severity scoring and detailed information about episodes of mechanical ventilation. The most widely used models for scoring the severity of illness of ICU patients include the Acute Physiology and Chronic Health Evaluation (APACHE), the Simplified Acute Physiology Score (SAPS), and the Mortality Prediction Model (MPM).1620 The APACHE II system is the most widely quoted in the medical literature but is based on a validation cohort more than 25 years old.16 The scoring algorithms for APACHE III and APACHE IV have been released on the Web; the most recent iteration, APACHE IV, was developed using data from more than 100,000 admissions to a variety of types of ICUs between January 1, 2002, and December 31, 2003, and also includes predictions for ICU LOS.18 Use of these tools allows the ICU clinician to benchmark the unit's performance against this large heterogeneous group of ICU patients treated using contemporary ICU practice patterns. Important features of mechanical ventilation episodes worth tracking include: time of start and finish of each episode (to calculate ventilator LOS); whether the patient had an unplanned extubation; the percentage of patients who required reintubation after planned extubation; tracheostomy rate; and the use of continuous intravenous sedatives or paralytics.
An advanced data outcome system would be linked to various hospital data silos, allowing capture of all laboratory, pharmacy, and radiology charges into the ICU database, allowing financial analysis of ICU performance. Another link would funnel all important laboratory results into the database. Additional types of useful data include: ultimate discharge status of the patient (eg, home, skilled nursing facility, rehabilitation facility, another acute care hospital); procedures done in the ICU; infections acquired in the ICU; and comorbidities based on ICD‐9 codes. Several examples of the output possible with the use of the advanced data outcome system developed for use in the Stamford Hospital ICU are reported later in this article.
Protocol‐driven collaborative culture
Successful implementation of TGC is most likely in an environment that embraces standardized care using evidence‐based best practices. All routine aspects of care in the Stamford Hospital ICU are protocol driven. Some examples include deep‐vein thrombosis prophylaxis, stress ulcer prophylaxis, ventilator weaning, ventilator sedation, enteral nutrition, and potassium, phosphate, and magnesium repletion. These protocols were all in place when discussions began in the ICU about how to create a TGC protocol. The nurses were comfortable using protocols, and there were no longer any counterproductive arguments about physician autonomy of treatment decisions centered on these basic care issues. These factors facilitated adoption of the TGC protocol. Finally, the strength of the relationship binding the nursing and medical leadership of the ICU was fundamental to the program's success. A complex initiative such as TGC mandates that these parties share the same vision for the ICU.
Overcoming resistance
Adoption of TGC by an ICU will undoubtedly encounter resistance from the staff. The factors responsible for this are very real. An understanding and patient attitude by the unit's leadership will greatly facilitate implementation. Factors that are the basis for this resistance in part include:
-
TGC represents a fundamental paradigm shift in ICU care. Until recently, hyperglycemia, even at levels as high as 200‐250 mg/dL, has until recently been tolerated and ignored, as it has been considered a normal adaptive response to acute and severe illness.
-
Doing TGC correctly is hard work. This work includes the logistics of monitoring, explaining to families and patients the reasons for frequent finger sticks or blood testing (But Grandma isn't even a diabetic), being aware of the potential for significant discomfort to the patient, and having to make treatment decisions in response to all the newly acquired data.
-
Fear of hypoglycemia. Nurses want to protect, and not hurt, their patients. Insulin therapy, especially when targeting euglycemia or near‐euglycemia, is potentially dangerous.
An effective educational program directed to the staff, including nurses, staff physicians, and pharmacists, will help surmount this resistance. The components of this educational program should include: the basis in the medical literature for instituting intensive programs to monitor and treat patient glycemic levels; a review of the insulin formulations (subcutaneous, intravenous, long acting, and short acting) with emphasis on the different pharmacokinetic implications underlying their use; and a detailed analysis of factors associated with hypoglycemia.21, 22
Specific Issues Regarding TGC Implementation
Setting the glycemic target
What is the correct glycemic target? Van den Berghe et al. used a treatment threshold of 110 mg/dL for both her surgical ICU and medical ICU studies. The Stamford Hospital ICU trial, with a mixed population of medical, surgical, and cardiac patients, targeted 140 mg/dL.13
A detailed review of a very large cohort of patients treated in the Stamford Hospital ICU suggests that patients who achieve low euglycemia have the best survival (see Fig. 3). This analysis used APACHE methodology to analyze expected and actual mortality in relation to each patient's mean glucose during the ICU stay. The APACHE III and IV mortality prediction models use age, presence or absence of a group of important comorbidities, admitting diagnosis to the ICU, length of time in the ICU before ICU admission, location of the patient prior to ICU admission, and the most abnormal values of a large group of physiological parameters during the first 24 hours of ICU admission to derive a discrete prediction of hospital mortality for that patient. A standardized mortality ratio (SMR) can be calculated by dividing the patients' actual hospital mortality rate by the mean of all the individual predictions of mortality (SMR = actual/predicted mortality). A value less than 1 suggests that the patients in the observed cohort had a lower mortality rate than that predicted by the model.
Patients who achieved euglycemia (<110 mg/dL) in the surgical ICU study of Van den Berghe et al. also had the lowest mortality rates as well as the lowest incidence of the various comorbidities measured compared to those with intermediate blood glucose levels (110‐150 mg/dL). Those with the worst glycemic control (blood glucose > 150 mg/dL) had the highest mortality rate and the highest incidence of various serious comorbid conditions.23
Although available data support a euglycemic target, is this unequivocally the correct target for an ICU beginning TGC implementation? Not necessarily. Targeting 110 mg/dL requires an intensity of treatment that may be intimidating to an ICU staff, especially one without experience managing protocols. Moreover, the lower the glycemic target, the greater the risk for iatrogenic hypoglycemia. An ICU considering implementation of a TGC protocol might consider staged adoption. The initial target might be as high as 175 mg/dL. As the clinicians gain experience using the protocol, including acquiring and reporting data, the treatment threshold could be lowered. The Stamford Hospital ICU staff, with more than 5 years of experience developing a model of standardized care using evidence‐based best‐practice patient care protocols, spent several months arguing about the glycemic target when TGC was first discussed following publication of the initial Van den Berghe study.12 The director of Critical Care wanted to replicate Van den Berghe's work and urged a target of 110 mg/dL. The nurses refused. A compromise was reached: a 140 mg/dL treatment threshold. This confirms an important lesson: the ICU team must choose an achievable goal. It is noteworthy that after 2 years of successful use of the glucose 140 protocol, the Stamford Hospital ICU nurses initiated a revision of the protocol, deciding they wanted to target 125 mg/dL. Figure 4 illustrates the glycemic and mortality results comparing the last 3 years before TGC with the glucose 140 and glucose 125 periods.
Choosing a protocol
After choosing a glycemic target, the ICU leadership must agree on a protocol to achieve the objective. TGC protocols can be broadly characterized as directive or nondirective.
The Stamford Hospital ICU TGC protocol is an example of a nondirective protocol.13 The nursing staff considers the document a starting point for therapy decisions. Many patients receive insulin dosing at variance with the guidelines established by the document. A nurse is empowered to make these treatment decisions. This is not dissimilar to the process ICU nurses use when titrating a vasopressor to achieve a targeted goal for mean arterial pressure. Nondirective protocols are most suitable for ICU staffs that have had considerable prior experience using nurse‐driven protocols in an environment that supports and accepts standardized care.
A number of directive protocols have been published in the literature.24 Their unifying feature is the goal of prescribing a specific insulin dose for each set of circumstances a nurse may encounter. The patient's previous glucose level and the rate of change in glucose level are considered, and the document typically details the choices for insulin dosing in several columns based on the patient's previously documented sensitivity to insulin. Although this sort of protocol can be helpful in providing explicit guidance with insulin dosing, its complexity may impede adoption.
Another option is the use of tools that have been developed to assist an ICU in initiating and promulgating TGC protocols, including software applications that automatically calculate insulin dosing. Finally, work has been initiated on the development of monitors that provide near‐continuous monitoring of glucose levels at bedside.25, 26 Adoption of such monitoring will facilitate the implementation of TGC protocols because of its impact on eliminating the workflow burdens of intensive glycemic monitoring as well as markedly diminishing the risk of hypoglycemia.
Hypoglycemia
In the Van den Berghe et al. surgical ICU study, severe hypoglycemia, defined as a glucose level less than 40 mg/dL, occurred at least once among 5.1% of the patients in the intensively treated group versus in 0.8% of the patients in the conventionally treated group.12 The hypoglycemia was described as transient, a result of the frequency of monitoring during the study, and was not associated with overt adverse consequences. The incidence of severe hypoglycemia (<40 mg/dL) was described differently in the Stamford Hospital trial: 0.35% of all the values obtained during the baseline period, compared to 0.34% of those obtained during the treatment period, again without any overt adverse consequences.13 Nevertheless, it is not known with certainty whether having even a single episode of severe hypoglycemia independently contributes to the risk of mortality.
Vreisendorp recently identified a group of predisposing factors for the development of severe hypoglycemia among ICU patients undergoing TGC.21 The most important include: a decrease in the administration of nutrition without a concomitant change in insulin dosing; diabetes mellitus; insulin treatment; sepsis; inotropic support; and renal failure. The Stamford Hospital ICU TGC protocol document now includes a black box warning highlighting renal failure (associated with decreased clearance of administered insulin), hepatic failure, and sepsis (associated with decreased hepatic gluconeogenesis) as major risk factors for severe hypoglycemia. Ongoing reinforcement is necessary to encourage the ICU staff recognize these risk factors for severe hypoglycemia and respond by adopting more conservative insulin dosing and instituting more frequent glucose monitoring.
Economic Benefits of TGC
Recently published data support the economic benefits of intensive glycemic management. Van den Berghe et al. quantified costs attributable to ICU days, mechanical ventilation, and use of antibiotics, vasopressors, intotropic agents, and transfusions in the 2 treatment groups in their surgical ICU study. The savings per patient in the intensively treated group totaled $2638; mean LOS was 6.6 days.27, 28 Data from the Stamford Hospital ICU trial was analyzed differently, with quantification of all laboratory, pharmacy, and diagnostic imaging costs, as well as costs associated with ICU days, mechanical ventilation and days in the hospital after ICU discharge.29 The savings per patient in the intensively treated group totaled $1560. Notably, this occurred in the context of a much shorter LOS than that seen in the Belgian trial; mean and median LOS were only 3.4 and 1.7 days, respectively.
CONCLUSIONS
Intensive glycemic management of critically ill patients is emerging as a standard of care, based on data demonstrating its effectiveness in reducing mortality, morbidity, and costs. Intensive care unit staffs need to make important choices about the type of protocol most suitable for use, the glycemic target, and the mechanisms for avoiding hypoglycemia. The implementation of appropriate data management tools in a protocol‐driven environment that supports standardization of care will facilitate adoption of TGC.
The last 15 years have brought reports in the medical literature of exciting advances in describing the relationship between hyperglycemia and adverse outcomes in a variety of clinical contexts involving acutely ill patients.19 Hyperglycemia in hospitalized patients was long thought to be an adaptive mechanism and, at least in the intensive care setting, was rarely treated below threshold values of 225‐250 mg/dL. The pioneering work of Furnary et al. and the Portland Diabetic Project was the first to demonstrate that close monitoring and treatment of hyperglycemia in diabetic patients undergoing cardiovascular surgery decreased the occurrence of deep sternal wound infections, a dreaded postoperative complication.10 A second publication documented the steady decrease in mortality among these patients over the years as the group's glycemic target was steadily lowered.11 In the last several years the mortality rate of diabetic patients undergoing cardiovascular surgery has decreased so that it now approximates that of nondiabetics, eliminating the diabetic disadvantage. This work set the stage for the landmark Leuven study, performed at Catholic University in Belgium and published by Van den Berghe's group in 2001.12 This prospective, randomized, controlled study involving 1548 mechanically ventilated patients in a surgical intensive care unit, 63% of whom had undergone cardiovascular surgery, compared the outcomes of patients treated with continuous intravenous insulin to achieve euglycemia (80‐110 mg/dL) to those of a control group that received treatment only when glucose level exceeded 210 mg/dL. The outcomes including a 37% reduction in hospital mortality in the treated group and a 40%‐50% reduction in numerous morbid conditions, including the need for renal replacement therapy, prolonged mechanical ventilation, prolonged antibiotic use, and critical illness polyneuropathy, that spawned a paradigm shift in ICU medicine. A large before‐and‐after study performed in a mixed medical‐surgical ICU of a university‐affiliated community hospital confirmed the mortality benefits of glycemic management, using a more modest target of 80‐140 mg/dL.13 Finally, a prospective, randomized, controlled trial in a medical ICU population by the Leuven investigators reported improvement in several morbidities and a mortality advantage from intensive glycemic control, targeting 80‐100 mg/dL, among patients with ICU stays longer than 3 days.14 Consequently, intensive glycemic management of critically ill patients is rapidly becoming a worldwide standard of care, presenting an array of challenges to clinicians involved in the care of these patients. This article presents an overview of the issues surrounding promulgation of protocols implementing tight glycemic control (TGC).
Building Blocks for Implementation of a Successful TGC Protocol
Data management tools
According to Curtis et al., A successful quality project requires transparent and informative data reporting. In the absence of timely and informative data reporting, interest wanes and projects lose momentum. On the other hand, actionable and interpretable data empower the ICU team, affirm that quality improvement efforts are making a difference, and increase the chances for sustainability.15
It is impossible to build a successful TGC program without proper data management tools. Conceptually, there are 2 levels of data reporting. At a minimum, an ICU must develop methods to demonstrate the effect of the protocol on glycemic levels. Optimally, there should also be a mechanism to report clinical and even financial outcomes resulting from the work. Quite simply, without ready access to these types of data it is unlikely that ICU cliniciansnurses, dieticians, and physicianswill continue to do the hard work necessary to allow a TGC program to achieve sustained success.
Examples of glycemic reports
Figure 1 shows a simple and powerful graphic used in the Stamford Hospital ICUthe mean monthly glucose value. This simple calculation does not account for severity of illness or prevalence of underlying diabetes, but it is readily understood and easy to create. The run chart below demonstrates the ICU's success in first implementing a treatment threshold of 140 mg/dL and, later, a treatment threshold of 125 mg/dL.
Another tool used in the Stamford Hospital ICU is a histogram that shows the percentage of glucose values that fall within discrete increments. Figure 2 details the outcomes in 3 periods: pre‐TGC, glucose 140, and glucose 125. This type of display powerfully demonstrates how the TGC protocols resulted in a marked increase in euglycemic values and dramatically reduced marked hyperglycemia.
The ability to capture useful sorts of data like these requires the assistance of the hospital's information technology department to create a link from the laboratory database to a data repository that the ICU's glycemic champion can regularly access and that displays the data in graphic form. Purchasing a point‐of‐care data management application provides an alternative solution. These applications can provide detailed reports on a unit's glycemic control, such as those displayed in Figures 1 and 2; some also have the capacity to delineate data by unit, individual practitioner, and patient.
Outcome data
The facility of an ICU to report data on glycemic control in a timely manner fulfills the minimum data requirement for successful implementation of a TGC protocol. However, sustained success depends on the unit's capacity to report information on relevant outcomes. It is not enough for an ICU director to be able to tell the hospital administration that the mean glucose level has decreased, from 160 to 135 mg/dL, for example, 6 months after institution of such a labor‐intensive program. The more relevant information is whether this intervention has had an effect on severity‐adjusted mortality, length of stay, and important comorbid conditions such as ICU‐acquired infections.
With innumerable measures that an ICU nursing or medical director might want to track, how should the measures to use be chosen?
A data set for a beginner might include the following parameters: demographics, including age, sex, and, possibly, ethnicity; admission and discharge dates and times; length of stay (LOS), ideally measured in exact time rather than number of calendar days; diagnosis; and ICU and hospital survival. The ICU data manager must develop a system to validate each patient's final discharge status from the hospital; some patients survive the ICU stay but die before hospital discharge, which therefore affects the ICU's hospital mortality rate.
The intermediate level of outcome reporting might include 2 additional elements: severity scoring and detailed information about episodes of mechanical ventilation. The most widely used models for scoring the severity of illness of ICU patients include the Acute Physiology and Chronic Health Evaluation (APACHE), the Simplified Acute Physiology Score (SAPS), and the Mortality Prediction Model (MPM).1620 The APACHE II system is the most widely quoted in the medical literature but is based on a validation cohort more than 25 years old.16 The scoring algorithms for APACHE III and APACHE IV have been released on the Web; the most recent iteration, APACHE IV, was developed using data from more than 100,000 admissions to a variety of types of ICUs between January 1, 2002, and December 31, 2003, and also includes predictions for ICU LOS.18 Use of these tools allows the ICU clinician to benchmark the unit's performance against this large heterogeneous group of ICU patients treated using contemporary ICU practice patterns. Important features of mechanical ventilation episodes worth tracking include: time of start and finish of each episode (to calculate ventilator LOS); whether the patient had an unplanned extubation; the percentage of patients who required reintubation after planned extubation; tracheostomy rate; and the use of continuous intravenous sedatives or paralytics.
An advanced data outcome system would be linked to various hospital data silos, allowing capture of all laboratory, pharmacy, and radiology charges into the ICU database, allowing financial analysis of ICU performance. Another link would funnel all important laboratory results into the database. Additional types of useful data include: ultimate discharge status of the patient (eg, home, skilled nursing facility, rehabilitation facility, another acute care hospital); procedures done in the ICU; infections acquired in the ICU; and comorbidities based on ICD‐9 codes. Several examples of the output possible with the use of the advanced data outcome system developed for use in the Stamford Hospital ICU are reported later in this article.
Protocol‐driven collaborative culture
Successful implementation of TGC is most likely in an environment that embraces standardized care using evidence‐based best practices. All routine aspects of care in the Stamford Hospital ICU are protocol driven. Some examples include deep‐vein thrombosis prophylaxis, stress ulcer prophylaxis, ventilator weaning, ventilator sedation, enteral nutrition, and potassium, phosphate, and magnesium repletion. These protocols were all in place when discussions began in the ICU about how to create a TGC protocol. The nurses were comfortable using protocols, and there were no longer any counterproductive arguments about physician autonomy of treatment decisions centered on these basic care issues. These factors facilitated adoption of the TGC protocol. Finally, the strength of the relationship binding the nursing and medical leadership of the ICU was fundamental to the program's success. A complex initiative such as TGC mandates that these parties share the same vision for the ICU.
Overcoming resistance
Adoption of TGC by an ICU will undoubtedly encounter resistance from the staff. The factors responsible for this are very real. An understanding and patient attitude by the unit's leadership will greatly facilitate implementation. Factors that are the basis for this resistance in part include:
-
TGC represents a fundamental paradigm shift in ICU care. Until recently, hyperglycemia, even at levels as high as 200‐250 mg/dL, has until recently been tolerated and ignored, as it has been considered a normal adaptive response to acute and severe illness.
-
Doing TGC correctly is hard work. This work includes the logistics of monitoring, explaining to families and patients the reasons for frequent finger sticks or blood testing (But Grandma isn't even a diabetic), being aware of the potential for significant discomfort to the patient, and having to make treatment decisions in response to all the newly acquired data.
-
Fear of hypoglycemia. Nurses want to protect, and not hurt, their patients. Insulin therapy, especially when targeting euglycemia or near‐euglycemia, is potentially dangerous.
An effective educational program directed to the staff, including nurses, staff physicians, and pharmacists, will help surmount this resistance. The components of this educational program should include: the basis in the medical literature for instituting intensive programs to monitor and treat patient glycemic levels; a review of the insulin formulations (subcutaneous, intravenous, long acting, and short acting) with emphasis on the different pharmacokinetic implications underlying their use; and a detailed analysis of factors associated with hypoglycemia.21, 22
Specific Issues Regarding TGC Implementation
Setting the glycemic target
What is the correct glycemic target? Van den Berghe et al. used a treatment threshold of 110 mg/dL for both her surgical ICU and medical ICU studies. The Stamford Hospital ICU trial, with a mixed population of medical, surgical, and cardiac patients, targeted 140 mg/dL.13
A detailed review of a very large cohort of patients treated in the Stamford Hospital ICU suggests that patients who achieve low euglycemia have the best survival (see Fig. 3). This analysis used APACHE methodology to analyze expected and actual mortality in relation to each patient's mean glucose during the ICU stay. The APACHE III and IV mortality prediction models use age, presence or absence of a group of important comorbidities, admitting diagnosis to the ICU, length of time in the ICU before ICU admission, location of the patient prior to ICU admission, and the most abnormal values of a large group of physiological parameters during the first 24 hours of ICU admission to derive a discrete prediction of hospital mortality for that patient. A standardized mortality ratio (SMR) can be calculated by dividing the patients' actual hospital mortality rate by the mean of all the individual predictions of mortality (SMR = actual/predicted mortality). A value less than 1 suggests that the patients in the observed cohort had a lower mortality rate than that predicted by the model.
Patients who achieved euglycemia (<110 mg/dL) in the surgical ICU study of Van den Berghe et al. also had the lowest mortality rates as well as the lowest incidence of the various comorbidities measured compared to those with intermediate blood glucose levels (110‐150 mg/dL). Those with the worst glycemic control (blood glucose > 150 mg/dL) had the highest mortality rate and the highest incidence of various serious comorbid conditions.23
Although available data support a euglycemic target, is this unequivocally the correct target for an ICU beginning TGC implementation? Not necessarily. Targeting 110 mg/dL requires an intensity of treatment that may be intimidating to an ICU staff, especially one without experience managing protocols. Moreover, the lower the glycemic target, the greater the risk for iatrogenic hypoglycemia. An ICU considering implementation of a TGC protocol might consider staged adoption. The initial target might be as high as 175 mg/dL. As the clinicians gain experience using the protocol, including acquiring and reporting data, the treatment threshold could be lowered. The Stamford Hospital ICU staff, with more than 5 years of experience developing a model of standardized care using evidence‐based best‐practice patient care protocols, spent several months arguing about the glycemic target when TGC was first discussed following publication of the initial Van den Berghe study.12 The director of Critical Care wanted to replicate Van den Berghe's work and urged a target of 110 mg/dL. The nurses refused. A compromise was reached: a 140 mg/dL treatment threshold. This confirms an important lesson: the ICU team must choose an achievable goal. It is noteworthy that after 2 years of successful use of the glucose 140 protocol, the Stamford Hospital ICU nurses initiated a revision of the protocol, deciding they wanted to target 125 mg/dL. Figure 4 illustrates the glycemic and mortality results comparing the last 3 years before TGC with the glucose 140 and glucose 125 periods.
Choosing a protocol
After choosing a glycemic target, the ICU leadership must agree on a protocol to achieve the objective. TGC protocols can be broadly characterized as directive or nondirective.
The Stamford Hospital ICU TGC protocol is an example of a nondirective protocol.13 The nursing staff considers the document a starting point for therapy decisions. Many patients receive insulin dosing at variance with the guidelines established by the document. A nurse is empowered to make these treatment decisions. This is not dissimilar to the process ICU nurses use when titrating a vasopressor to achieve a targeted goal for mean arterial pressure. Nondirective protocols are most suitable for ICU staffs that have had considerable prior experience using nurse‐driven protocols in an environment that supports and accepts standardized care.
A number of directive protocols have been published in the literature.24 Their unifying feature is the goal of prescribing a specific insulin dose for each set of circumstances a nurse may encounter. The patient's previous glucose level and the rate of change in glucose level are considered, and the document typically details the choices for insulin dosing in several columns based on the patient's previously documented sensitivity to insulin. Although this sort of protocol can be helpful in providing explicit guidance with insulin dosing, its complexity may impede adoption.
Another option is the use of tools that have been developed to assist an ICU in initiating and promulgating TGC protocols, including software applications that automatically calculate insulin dosing. Finally, work has been initiated on the development of monitors that provide near‐continuous monitoring of glucose levels at bedside.25, 26 Adoption of such monitoring will facilitate the implementation of TGC protocols because of its impact on eliminating the workflow burdens of intensive glycemic monitoring as well as markedly diminishing the risk of hypoglycemia.
Hypoglycemia
In the Van den Berghe et al. surgical ICU study, severe hypoglycemia, defined as a glucose level less than 40 mg/dL, occurred at least once among 5.1% of the patients in the intensively treated group versus in 0.8% of the patients in the conventionally treated group.12 The hypoglycemia was described as transient, a result of the frequency of monitoring during the study, and was not associated with overt adverse consequences. The incidence of severe hypoglycemia (<40 mg/dL) was described differently in the Stamford Hospital trial: 0.35% of all the values obtained during the baseline period, compared to 0.34% of those obtained during the treatment period, again without any overt adverse consequences.13 Nevertheless, it is not known with certainty whether having even a single episode of severe hypoglycemia independently contributes to the risk of mortality.
Vreisendorp recently identified a group of predisposing factors for the development of severe hypoglycemia among ICU patients undergoing TGC.21 The most important include: a decrease in the administration of nutrition without a concomitant change in insulin dosing; diabetes mellitus; insulin treatment; sepsis; inotropic support; and renal failure. The Stamford Hospital ICU TGC protocol document now includes a black box warning highlighting renal failure (associated with decreased clearance of administered insulin), hepatic failure, and sepsis (associated with decreased hepatic gluconeogenesis) as major risk factors for severe hypoglycemia. Ongoing reinforcement is necessary to encourage the ICU staff recognize these risk factors for severe hypoglycemia and respond by adopting more conservative insulin dosing and instituting more frequent glucose monitoring.
Economic Benefits of TGC
Recently published data support the economic benefits of intensive glycemic management. Van den Berghe et al. quantified costs attributable to ICU days, mechanical ventilation, and use of antibiotics, vasopressors, intotropic agents, and transfusions in the 2 treatment groups in their surgical ICU study. The savings per patient in the intensively treated group totaled $2638; mean LOS was 6.6 days.27, 28 Data from the Stamford Hospital ICU trial was analyzed differently, with quantification of all laboratory, pharmacy, and diagnostic imaging costs, as well as costs associated with ICU days, mechanical ventilation and days in the hospital after ICU discharge.29 The savings per patient in the intensively treated group totaled $1560. Notably, this occurred in the context of a much shorter LOS than that seen in the Belgian trial; mean and median LOS were only 3.4 and 1.7 days, respectively.
CONCLUSIONS
Intensive glycemic management of critically ill patients is emerging as a standard of care, based on data demonstrating its effectiveness in reducing mortality, morbidity, and costs. Intensive care unit staffs need to make important choices about the type of protocol most suitable for use, the glycemic target, and the mechanisms for avoiding hypoglycemia. The implementation of appropriate data management tools in a protocol‐driven environment that supports standardization of care will facilitate adoption of TGC.
- .Hyperglycemia during critical illness.J Parenter Enteral Nutr.2006;30:254–258.
- ,,, et al.Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview.Lancet.2000;355:773–778.
- .Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus.DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group.BMJ.1997;314:1512–1515.
- ,,, et al.Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview.Stroke.2001;32:2426–2432.
- ,,, et al.Admission glucose level and clinical outcomes in the NINDS rt‐PA Stroke Trial.Neurology.2002;59:669–674.
- ,,, et al.Outcomes and perioperative hyperglycemia in patients with or without diabetes mellitus undergoing coronary artery bypass grafting.Ann Thorac Surg.2003;75:1392–1399.
- ,,.Admission hyperglycemia as a prognostic indicator in trauma.J Trauma.2003;55:33–38.
- ,,.Perioperative diabetic and hyperglycemic management issues.Crit Care Med.2004;32:S116–S125.
- .Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients.Mayo Clinic Proc.2003;78:1471–1478.
- ,,, et al.Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures.Ann Thorac Surg.1999;67:352–360.
- ,,, et al.Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting.J Thorac Cardiovasc Surg.2003;125:1007–1021.
- ,,, et al.Intensive insulin therapy in the critically ill patients.N Engl J Med.2001;345:1359–1367.
- .Effect of an intensive glucose management protocol on the mortality of critically ill adult patients.Mayo Clin Proc.2004;79:992–1000.
- ,,, et al.Intensive insulin therapy in the medical ICU.N Engl J Med.2006;354:449–461.
- ,,, et al.Intensive care unit quality improvement: A “how‐to” guide for the interdisciplinary team.Crit Care Med.2006;34:211–218.
- ,,, et al.APACHE II. A severity of disease classification system.Crit Care Med.1985;13:818–829.
- ,,, et al.The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults.Chest.1991;100:1619–1636.
- http://www.cerner.com/public/Cerner_3.asp?id=3562. Accessed December 12,2006.
- ,,, et al.SAPS II revisited.Int Care Med.2005;31:416–423.
- ,,, et al.Mortality probability models (MPM II) based on an international cohort of intensive care unit patients.JAMA.1993;270:2478–86.
- ,,, et al.Predisposing factors for hypoglycemia in the intensive care unit.Crit Care Med.2006;34:96–101.
- ,,, et al.Evaluation of short‐term outcomes of hypoglycemia in the intensive care unit.Crit Care Med.2006;34:2714–1218.
- ,,, et al.Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control.Crit Care Med.2003;31:359–366.
- http://www.glycemiccontrol.net/Published_Protocols.htm. Accessed December 12,2006.
- ,,, et al.Validation of the OptiScanner, a new continuous glucose monitor.Crit Care Med.2005;33:S265.
- ,,, et al.ICU validation of the OptiScanner, a continuous glucose monitoring device.Crit Care Med.2006;34:A67.
- ,,, et al.Analysis of healthcare resource utilization with intensive insulin therapy in critically ill patients.Crit Care Med.2006;34:612–616.
- .A simple intervention that saves lives and money.Crit Care Med.2006;34:896.
- ,.Cost analysis of intensive glycemic control in critically ill adult patients.Chest.2006;129:644–650.
- .Hyperglycemia during critical illness.J Parenter Enteral Nutr.2006;30:254–258.
- ,,, et al.Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview.Lancet.2000;355:773–778.
- .Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus.DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group.BMJ.1997;314:1512–1515.
- ,,, et al.Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview.Stroke.2001;32:2426–2432.
- ,,, et al.Admission glucose level and clinical outcomes in the NINDS rt‐PA Stroke Trial.Neurology.2002;59:669–674.
- ,,, et al.Outcomes and perioperative hyperglycemia in patients with or without diabetes mellitus undergoing coronary artery bypass grafting.Ann Thorac Surg.2003;75:1392–1399.
- ,,.Admission hyperglycemia as a prognostic indicator in trauma.J Trauma.2003;55:33–38.
- ,,.Perioperative diabetic and hyperglycemic management issues.Crit Care Med.2004;32:S116–S125.
- .Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients.Mayo Clinic Proc.2003;78:1471–1478.
- ,,, et al.Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures.Ann Thorac Surg.1999;67:352–360.
- ,,, et al.Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting.J Thorac Cardiovasc Surg.2003;125:1007–1021.
- ,,, et al.Intensive insulin therapy in the critically ill patients.N Engl J Med.2001;345:1359–1367.
- .Effect of an intensive glucose management protocol on the mortality of critically ill adult patients.Mayo Clin Proc.2004;79:992–1000.
- ,,, et al.Intensive insulin therapy in the medical ICU.N Engl J Med.2006;354:449–461.
- ,,, et al.Intensive care unit quality improvement: A “how‐to” guide for the interdisciplinary team.Crit Care Med.2006;34:211–218.
- ,,, et al.APACHE II. A severity of disease classification system.Crit Care Med.1985;13:818–829.
- ,,, et al.The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults.Chest.1991;100:1619–1636.
- http://www.cerner.com/public/Cerner_3.asp?id=3562. Accessed December 12,2006.
- ,,, et al.SAPS II revisited.Int Care Med.2005;31:416–423.
- ,,, et al.Mortality probability models (MPM II) based on an international cohort of intensive care unit patients.JAMA.1993;270:2478–86.
- ,,, et al.Predisposing factors for hypoglycemia in the intensive care unit.Crit Care Med.2006;34:96–101.
- ,,, et al.Evaluation of short‐term outcomes of hypoglycemia in the intensive care unit.Crit Care Med.2006;34:2714–1218.
- ,,, et al.Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control.Crit Care Med.2003;31:359–366.
- http://www.glycemiccontrol.net/Published_Protocols.htm. Accessed December 12,2006.
- ,,, et al.Validation of the OptiScanner, a new continuous glucose monitor.Crit Care Med.2005;33:S265.
- ,,, et al.ICU validation of the OptiScanner, a continuous glucose monitoring device.Crit Care Med.2006;34:A67.
- ,,, et al.Analysis of healthcare resource utilization with intensive insulin therapy in critically ill patients.Crit Care Med.2006;34:612–616.
- .A simple intervention that saves lives and money.Crit Care Med.2006;34:896.
- ,.Cost analysis of intensive glycemic control in critically ill adult patients.Chest.2006;129:644–650.
Tight Glycemic Control / Michota and Braithwaite
Hyperglycemia is common in the hospital among patients with diabetes and those without. The exact overall prevalence of diabetes in the hospital is unknown; however, in 2000, 12.4% of U.S. hospital discharges listed diabetes as a diagnosis. Among cardiac surgery patients, the prevalence of diabetes is as high as 29%.2 Another study reported a 26% prevalence of diabetes in a community teaching hospital, with an additional 12% of patients having unrecognized diabetes or hospital‐related hyperglycemia.3 Levetan et al. found laboratory‐documented hyperglycemia in 13% of 1034 consecutively hospitalized patients.4 A subsequent chart review found that more than one‐third of patients with hyperglycemia identified by laboratory testing remained unrecognized as having diabetes documented in the discharge summary, although diabetes or hyperglycemia was noted in the progress notes. In a retrospective chart review study, Umpierrez et al. similarly found 38% of 1886 consecutively hospitalized patients who had glucose measurements on admission were hyperglycemic.3 One‐third of these patients were not previously known to have diabetes, and compared to patients with diagnosed diabetes, they were more likely to require admission to the intensive care unit, had longer hospital stays, and were less likely to be discharged straight home.
Until recently, most clinicians viewed tight glucose control in the hospitalized patient as an intervention with little immediate benefit and significant potential for harm. The goal was simply to prevent excessive hyperglycemia and avoid ketoacidosis or significant fluid derangements while minimizing the risk for hypoglycemia. Today, a growing body of evidence suggests a close correlation between tight glucose control and improved clinical outcomes. Among those who have had a myocardial infarction and those in the surgical intensive care unit, it is known that intensive glycemic control reduces mortality.5, 6 Maintaining normoglycemia in patients in the surgical intensive care unit through intravenous insulin infusion also reduces the incidence of comorbidities such as transfusion requirements, renal failure, sepsis, and neuropathy and reduces the duration of ventilator dependence.6 Although trials using glucose‐insulin‐potassium infusions (GIK), when conducted such that lowering of blood glucose occurred, have shown benefit in the settings of myocardial infarction5, 7 and cardiac surgery,8 not all studies of GIK therapy have yielded positive results. The negative results of the CREATE‐ECLA study suggest that GIK therapy per se is not beneficial unless it reduces blood glucose.9 An abundance of additional observational data and comparisons with historical control data suggest that favorable outcomes might be causally dependent on euglycemia. The outcomes studied include hospital or critical care unit mortality and nosocomial infection,1014 specifically outcomes of strokes,1522 trauma,2325 renal transplantation,2628 myocardial infarction,2936 endocarditis,37 acute lymphocytic leukemia,38 community‐acquired pneumonia,39 infectious complications in the hospital,4046 and cardiac surgery,9, 44, 45, 4751 as well as length of stay and costs.11, 25, 5156
It is important for each hospital to consider the methodology used for blood glucose measurement, realizing that measurements in the Leuven Belgium studies were performed on arterial whole blood using a blood gas analyzer. With recognition that the normal range for blood glucose is method dependent, the data presented above form the basis for the recommended glycemic targets for hospitalized patients:
Target range blood glucose (AACE et al., 2004)
-
Preprandial: < 110 mg/dL
-
Peak postprandial: < 180 mg/dL
-
Critically ill surgical patients: 80‐110 mg/dL Target range blood glucose (ADA, 2006)
-
Critically ill: Blood glucose as close to 110 mg/dL as possible and generally < 180 mg/dL. These patients generally will require IV insulin.
-
Noncritically ill: Premeal blood glucose as close to 90‐130 mg/dL as possible (midpoint 110 mg/dL). Postprandial blood glucose < 180 mg/dL.
This supplement, Avoiding Complications in the Hospitalized Patient: The Case for Tight Glycemic Control, reviews several aspects of hyperglycemia in the hospital setting. Evidence that supports more intensive glucose control is reviewed, along with a real‐world success story that demonstrates how to apply the new glycemic targets in a multidisciplinary performance improvement project. In addition, the standard insulin sliding scale is examined in terms of efficacy, safety, and potential for meeting the new recommended glycemic targets.
- Tierney E: Data from the national hospital discharge survey database 2000.Centers for Disease Control and Prevention, Division of Diabetes translation,Atlanta, GA,2003.
- Moghissi E: Hospital management of diabetes: beyond the sliding scale.Clev Clin J Med.2004;71:801–808.
- ,,,,,.Hyperglycemia: an independent marker of in‐hospital mortality in patients with undiagnosed diabetes.J Clin Endocrinol Metab.2002;87:978–982.
- ,,,,Ratner RE: Unrecognized diabetes among hospitalized patients.Diabetes Care.1998;21:246–249.
- , for theDIGAMI study group.Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus.BMJ.1997;314:1512–1515.
- ,,, et al.Intensive insulin therapy in critically ill patients.N Engl J Med.2001;345:1359–1367.
- ,,, et al.Randomized trial of insulin‐glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year.J Am Coll Cardiol.1995;26:57–65.
- ,,,,,.Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.Circulation.2004;109:1497–1502.
- CREATE‐ECLA Trial Group Investigators.Effect of glucose‐insulin‐potassium infusion on mortality in patients with acute st‐segment elevation myocardial infarction: the CREATE‐ECLA randomized controlled trial.JAMA.2005;293:437–446.
- ,,, et al.Intensive insulin therapy in the medical ICU.N Engl J Med.2006;354:449–461.
- ,.Reduction of nosocomial infections in the surgical intensive‐care unit by strict glycemic control.Endocr Pract.2004;10(suppl 2):46–52.
- ,,, et al.Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting.J Thorac Cardiovasc Surg.2003;125:1007–1021.
- ,,,,,.Mortalilty in hospitalized patients with hypoglycemia and severe hyperglycemia.Mt Sinai J Med.1995;62:422–426.
- ,,,,,.Hyperglycemia: an independent marker of in‐hospital mortality in patients with undiagnosed diabetes.J Clin Endocrinol Metab.2002;87:978–982.
- ,,,.Glucose control and mortality in critically ill patients.JAMA.2003;290:2041–2047.
- .Effect of an intensive glucose management protocol on the mortality of critically ill adult patients.Mayo Clin Proc.2004:79:992–1000.
- ,,.Insulin therapy for critically ill hospitalized patients: a meta‐analysis of randomized controlled trials.Arch Intern Med.2004;164:2005–2011.
- ,,, et al.Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome.Stroke.2003;34:2208–2214.
- ,,,,.Stress hyperglycemia and prognosis of stroke in nodiabetic and diabetic patients: a systematic overview.Stroke.2001;32:2426–2432.
- ,,, et al.Admission glucose level and clinical outcomes in the NINDS rt‐PA Stroke Trial.Neurology.2002;59:669–674.
- .Effect of hyperglycemia on stroke outcomes.Endocr Pract.2004;10(suppl 2):34–39.
- ,,, et al.Predictors of hyperacute clinical worsening in ischemic stroke patients receiving thrombolytic therapy.Stroke.2004;35:1903–1907.
- ,.Hyperglycemia in acute stroke.Stroke.2004;35:363–364.
- ,,,,.Decreased mortality by normalizing blood glucose after acute ischemic stroke.Acad Emerg Med.2006;13:174–180.
- ,,.Blood glucose control after acute stroke: a retrospective study.Acad Emerg Med.2003;10:432.
- ,,,,.Relationship of early hyperglycemia to mortality in trauma patients.J Trauma.2004;56:1058–1062.
- ,,,,,.Admission hyperglycemia is predictive of outcome in critically ill trauma patients.J Trauma.2005;59:80–83.
- ,,, et al.Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke.Neurology.2002;59(1):67–71.
- ,,,,.Early peri‐operative glycaemic control and allograft rejection in patients with diabetes mellitus: a pilot study.Transplantation.2001;72:1321–1324.
- ,,,,.Early peri‐operative hyperglycaemia and renal allograft rejection in patients without diabetes.BMC Nephrol.2000;1:1.
- ,,,,.Protective effect of insulin on ischemic renal injury in diabetes mellitus.Kidney Int.2002;61:1383–1392.
- ,,,,,.Impaired glucose metabolism predicts mortality after a myocardial infarction.Int J Cardiol.2001;79 (2–3):207–214.
- ,,,.Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview.Lancet.2000;355:773–778.
- ,,, et al.A single serum glucose measurement predicts adverse outcomes across the whole range of acute coronary syndromes.Heart.2003;89:512–516.
- ,,,,,.Intensification of therapeutic approaches reduces mortality in diabetic patients with acute myocardial infarction: the Munich registry.Diabetes Care.2004;27:455–460.
- ,,, et al.Admission blood glucose level as risk indicator of death after myocardial infarction in patients with and without diabetes mellitus.Arch Intern Med.2004;164:982–988.
- ,,,.Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long‐term results from the diabetes and insulin‐glucose infusion in acute myocardial infarction (DIGAMI) study.Circulation.1999;99:2626–2632.
- ,,,,,.Plasma glucose at hospital admission and previous metabolic control determine myocardial infarct size and survival in patients with and without type 2 diabetes: the Langendreer Myocardial Infarction and Blood Glucose in Diabetic Patients Assessment (LAMBDA).Diabetes Care.2005;28:2551–2553.
- ,,, et al.Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes.Circulation.2005;111:3078–3086.
- ,,, et al.Early predictors of in‐hospital death in infective endocarditis.Circulation.2004;109:1745–1749.
- .Relation between the duration of remission and hyperglycemia in induction chemotherapy for acute lymphocytic leukemia.Cancer.2004;100:1179–1185.
- ,,,,.Etiology and outcome of community‐acquired pneumonia in patients with diabetes mellitus.Chest.2005;128:3233–3239.
- ,,,.Perioperative glycemic control and the risk of infectious complications in a cohort of adults with diabetes.Diabetes Care.1999;22:1408–1414.
- ,,, et al.Early postoperative glucose control predicts nosocomial infection rate in diabetic patients.J Parenter Enteral Nutr.1998;22(2):77–81.
- ,,,,.The association of diabetes and glucose control with surgical‐site infections among cardiothoracic surgery patients.Infect Control Hosp Epidemiol.2001;22:607–612.
- ,,,,.Early post‐operative glucose levels are an independent risk factor for infection after peripheral vascular surgery. A retrospective study.Eur J Vasc Endovasc Surg.2004;5:520–525.
- ,,.Glucose control lowers the risk of wound infection in diabetics after open heart operations.Ann Thorac Surg.1997;63:356–61.
- ,,,.Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures.Ann Thorac Surg.1999;67:352–362.
- ,,, et al.Improving outcomes for diabetic patients undergoing vascular surgery.Diabetes Spectr.2005;18(1):53–60.
- ,,.Early postoperative outcome and medium‐term survival in 540 diabetic and 2239 nondiabetic patients undergoing coronary artery bypass grafting.Ann Thorac Surg.2002;74:712–719.
- ,,,,.Diabetes and coronary artery bypass surgery: an examination of perioperative glycemic control and outcomes.Diabetes Care.2003;26:1518–1524.
- ,,.Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland diabetic project.Endocr Pract.2004;10(suppl 2):21–33.
- ,,,,.Glucose‐insulin‐potassium solutions improve outcomes in diabetics who have coronary artery operations.Ann Thorac Surg.2000;70:145–150.
- ,,, et al.Intraoperative hyperglycemia and perioperative outcomes in cardiac surgery patients.Mayo Clin Proc.2005;80:862–866.
- ,,,.Postoperative hyperglycemia prolongs length of stay in diabetic CABG patients.Circulation. II2000;102(II):556 (abstract).
- .Reduction of hospital costs and length of stay by good control of blood glucose levels.Endocr Pract.2004;10(suppl 2):53–56.
Hyperglycemia is common in the hospital among patients with diabetes and those without. The exact overall prevalence of diabetes in the hospital is unknown; however, in 2000, 12.4% of U.S. hospital discharges listed diabetes as a diagnosis. Among cardiac surgery patients, the prevalence of diabetes is as high as 29%.2 Another study reported a 26% prevalence of diabetes in a community teaching hospital, with an additional 12% of patients having unrecognized diabetes or hospital‐related hyperglycemia.3 Levetan et al. found laboratory‐documented hyperglycemia in 13% of 1034 consecutively hospitalized patients.4 A subsequent chart review found that more than one‐third of patients with hyperglycemia identified by laboratory testing remained unrecognized as having diabetes documented in the discharge summary, although diabetes or hyperglycemia was noted in the progress notes. In a retrospective chart review study, Umpierrez et al. similarly found 38% of 1886 consecutively hospitalized patients who had glucose measurements on admission were hyperglycemic.3 One‐third of these patients were not previously known to have diabetes, and compared to patients with diagnosed diabetes, they were more likely to require admission to the intensive care unit, had longer hospital stays, and were less likely to be discharged straight home.
Until recently, most clinicians viewed tight glucose control in the hospitalized patient as an intervention with little immediate benefit and significant potential for harm. The goal was simply to prevent excessive hyperglycemia and avoid ketoacidosis or significant fluid derangements while minimizing the risk for hypoglycemia. Today, a growing body of evidence suggests a close correlation between tight glucose control and improved clinical outcomes. Among those who have had a myocardial infarction and those in the surgical intensive care unit, it is known that intensive glycemic control reduces mortality.5, 6 Maintaining normoglycemia in patients in the surgical intensive care unit through intravenous insulin infusion also reduces the incidence of comorbidities such as transfusion requirements, renal failure, sepsis, and neuropathy and reduces the duration of ventilator dependence.6 Although trials using glucose‐insulin‐potassium infusions (GIK), when conducted such that lowering of blood glucose occurred, have shown benefit in the settings of myocardial infarction5, 7 and cardiac surgery,8 not all studies of GIK therapy have yielded positive results. The negative results of the CREATE‐ECLA study suggest that GIK therapy per se is not beneficial unless it reduces blood glucose.9 An abundance of additional observational data and comparisons with historical control data suggest that favorable outcomes might be causally dependent on euglycemia. The outcomes studied include hospital or critical care unit mortality and nosocomial infection,1014 specifically outcomes of strokes,1522 trauma,2325 renal transplantation,2628 myocardial infarction,2936 endocarditis,37 acute lymphocytic leukemia,38 community‐acquired pneumonia,39 infectious complications in the hospital,4046 and cardiac surgery,9, 44, 45, 4751 as well as length of stay and costs.11, 25, 5156
It is important for each hospital to consider the methodology used for blood glucose measurement, realizing that measurements in the Leuven Belgium studies were performed on arterial whole blood using a blood gas analyzer. With recognition that the normal range for blood glucose is method dependent, the data presented above form the basis for the recommended glycemic targets for hospitalized patients:
Target range blood glucose (AACE et al., 2004)
-
Preprandial: < 110 mg/dL
-
Peak postprandial: < 180 mg/dL
-
Critically ill surgical patients: 80‐110 mg/dL Target range blood glucose (ADA, 2006)
-
Critically ill: Blood glucose as close to 110 mg/dL as possible and generally < 180 mg/dL. These patients generally will require IV insulin.
-
Noncritically ill: Premeal blood glucose as close to 90‐130 mg/dL as possible (midpoint 110 mg/dL). Postprandial blood glucose < 180 mg/dL.
This supplement, Avoiding Complications in the Hospitalized Patient: The Case for Tight Glycemic Control, reviews several aspects of hyperglycemia in the hospital setting. Evidence that supports more intensive glucose control is reviewed, along with a real‐world success story that demonstrates how to apply the new glycemic targets in a multidisciplinary performance improvement project. In addition, the standard insulin sliding scale is examined in terms of efficacy, safety, and potential for meeting the new recommended glycemic targets.
Hyperglycemia is common in the hospital among patients with diabetes and those without. The exact overall prevalence of diabetes in the hospital is unknown; however, in 2000, 12.4% of U.S. hospital discharges listed diabetes as a diagnosis. Among cardiac surgery patients, the prevalence of diabetes is as high as 29%.2 Another study reported a 26% prevalence of diabetes in a community teaching hospital, with an additional 12% of patients having unrecognized diabetes or hospital‐related hyperglycemia.3 Levetan et al. found laboratory‐documented hyperglycemia in 13% of 1034 consecutively hospitalized patients.4 A subsequent chart review found that more than one‐third of patients with hyperglycemia identified by laboratory testing remained unrecognized as having diabetes documented in the discharge summary, although diabetes or hyperglycemia was noted in the progress notes. In a retrospective chart review study, Umpierrez et al. similarly found 38% of 1886 consecutively hospitalized patients who had glucose measurements on admission were hyperglycemic.3 One‐third of these patients were not previously known to have diabetes, and compared to patients with diagnosed diabetes, they were more likely to require admission to the intensive care unit, had longer hospital stays, and were less likely to be discharged straight home.
Until recently, most clinicians viewed tight glucose control in the hospitalized patient as an intervention with little immediate benefit and significant potential for harm. The goal was simply to prevent excessive hyperglycemia and avoid ketoacidosis or significant fluid derangements while minimizing the risk for hypoglycemia. Today, a growing body of evidence suggests a close correlation between tight glucose control and improved clinical outcomes. Among those who have had a myocardial infarction and those in the surgical intensive care unit, it is known that intensive glycemic control reduces mortality.5, 6 Maintaining normoglycemia in patients in the surgical intensive care unit through intravenous insulin infusion also reduces the incidence of comorbidities such as transfusion requirements, renal failure, sepsis, and neuropathy and reduces the duration of ventilator dependence.6 Although trials using glucose‐insulin‐potassium infusions (GIK), when conducted such that lowering of blood glucose occurred, have shown benefit in the settings of myocardial infarction5, 7 and cardiac surgery,8 not all studies of GIK therapy have yielded positive results. The negative results of the CREATE‐ECLA study suggest that GIK therapy per se is not beneficial unless it reduces blood glucose.9 An abundance of additional observational data and comparisons with historical control data suggest that favorable outcomes might be causally dependent on euglycemia. The outcomes studied include hospital or critical care unit mortality and nosocomial infection,1014 specifically outcomes of strokes,1522 trauma,2325 renal transplantation,2628 myocardial infarction,2936 endocarditis,37 acute lymphocytic leukemia,38 community‐acquired pneumonia,39 infectious complications in the hospital,4046 and cardiac surgery,9, 44, 45, 4751 as well as length of stay and costs.11, 25, 5156
It is important for each hospital to consider the methodology used for blood glucose measurement, realizing that measurements in the Leuven Belgium studies were performed on arterial whole blood using a blood gas analyzer. With recognition that the normal range for blood glucose is method dependent, the data presented above form the basis for the recommended glycemic targets for hospitalized patients:
Target range blood glucose (AACE et al., 2004)
-
Preprandial: < 110 mg/dL
-
Peak postprandial: < 180 mg/dL
-
Critically ill surgical patients: 80‐110 mg/dL Target range blood glucose (ADA, 2006)
-
Critically ill: Blood glucose as close to 110 mg/dL as possible and generally < 180 mg/dL. These patients generally will require IV insulin.
-
Noncritically ill: Premeal blood glucose as close to 90‐130 mg/dL as possible (midpoint 110 mg/dL). Postprandial blood glucose < 180 mg/dL.
This supplement, Avoiding Complications in the Hospitalized Patient: The Case for Tight Glycemic Control, reviews several aspects of hyperglycemia in the hospital setting. Evidence that supports more intensive glucose control is reviewed, along with a real‐world success story that demonstrates how to apply the new glycemic targets in a multidisciplinary performance improvement project. In addition, the standard insulin sliding scale is examined in terms of efficacy, safety, and potential for meeting the new recommended glycemic targets.
- Tierney E: Data from the national hospital discharge survey database 2000.Centers for Disease Control and Prevention, Division of Diabetes translation,Atlanta, GA,2003.
- Moghissi E: Hospital management of diabetes: beyond the sliding scale.Clev Clin J Med.2004;71:801–808.
- ,,,,,.Hyperglycemia: an independent marker of in‐hospital mortality in patients with undiagnosed diabetes.J Clin Endocrinol Metab.2002;87:978–982.
- ,,,,Ratner RE: Unrecognized diabetes among hospitalized patients.Diabetes Care.1998;21:246–249.
- , for theDIGAMI study group.Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus.BMJ.1997;314:1512–1515.
- ,,, et al.Intensive insulin therapy in critically ill patients.N Engl J Med.2001;345:1359–1367.
- ,,, et al.Randomized trial of insulin‐glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year.J Am Coll Cardiol.1995;26:57–65.
- ,,,,,.Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.Circulation.2004;109:1497–1502.
- CREATE‐ECLA Trial Group Investigators.Effect of glucose‐insulin‐potassium infusion on mortality in patients with acute st‐segment elevation myocardial infarction: the CREATE‐ECLA randomized controlled trial.JAMA.2005;293:437–446.
- ,,, et al.Intensive insulin therapy in the medical ICU.N Engl J Med.2006;354:449–461.
- ,.Reduction of nosocomial infections in the surgical intensive‐care unit by strict glycemic control.Endocr Pract.2004;10(suppl 2):46–52.
- ,,, et al.Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting.J Thorac Cardiovasc Surg.2003;125:1007–1021.
- ,,,,,.Mortalilty in hospitalized patients with hypoglycemia and severe hyperglycemia.Mt Sinai J Med.1995;62:422–426.
- ,,,,,.Hyperglycemia: an independent marker of in‐hospital mortality in patients with undiagnosed diabetes.J Clin Endocrinol Metab.2002;87:978–982.
- ,,,.Glucose control and mortality in critically ill patients.JAMA.2003;290:2041–2047.
- .Effect of an intensive glucose management protocol on the mortality of critically ill adult patients.Mayo Clin Proc.2004:79:992–1000.
- ,,.Insulin therapy for critically ill hospitalized patients: a meta‐analysis of randomized controlled trials.Arch Intern Med.2004;164:2005–2011.
- ,,, et al.Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome.Stroke.2003;34:2208–2214.
- ,,,,.Stress hyperglycemia and prognosis of stroke in nodiabetic and diabetic patients: a systematic overview.Stroke.2001;32:2426–2432.
- ,,, et al.Admission glucose level and clinical outcomes in the NINDS rt‐PA Stroke Trial.Neurology.2002;59:669–674.
- .Effect of hyperglycemia on stroke outcomes.Endocr Pract.2004;10(suppl 2):34–39.
- ,,, et al.Predictors of hyperacute clinical worsening in ischemic stroke patients receiving thrombolytic therapy.Stroke.2004;35:1903–1907.
- ,.Hyperglycemia in acute stroke.Stroke.2004;35:363–364.
- ,,,,.Decreased mortality by normalizing blood glucose after acute ischemic stroke.Acad Emerg Med.2006;13:174–180.
- ,,.Blood glucose control after acute stroke: a retrospective study.Acad Emerg Med.2003;10:432.
- ,,,,.Relationship of early hyperglycemia to mortality in trauma patients.J Trauma.2004;56:1058–1062.
- ,,,,,.Admission hyperglycemia is predictive of outcome in critically ill trauma patients.J Trauma.2005;59:80–83.
- ,,, et al.Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke.Neurology.2002;59(1):67–71.
- ,,,,.Early peri‐operative glycaemic control and allograft rejection in patients with diabetes mellitus: a pilot study.Transplantation.2001;72:1321–1324.
- ,,,,.Early peri‐operative hyperglycaemia and renal allograft rejection in patients without diabetes.BMC Nephrol.2000;1:1.
- ,,,,.Protective effect of insulin on ischemic renal injury in diabetes mellitus.Kidney Int.2002;61:1383–1392.
- ,,,,,.Impaired glucose metabolism predicts mortality after a myocardial infarction.Int J Cardiol.2001;79 (2–3):207–214.
- ,,,.Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview.Lancet.2000;355:773–778.
- ,,, et al.A single serum glucose measurement predicts adverse outcomes across the whole range of acute coronary syndromes.Heart.2003;89:512–516.
- ,,,,,.Intensification of therapeutic approaches reduces mortality in diabetic patients with acute myocardial infarction: the Munich registry.Diabetes Care.2004;27:455–460.
- ,,, et al.Admission blood glucose level as risk indicator of death after myocardial infarction in patients with and without diabetes mellitus.Arch Intern Med.2004;164:982–988.
- ,,,.Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long‐term results from the diabetes and insulin‐glucose infusion in acute myocardial infarction (DIGAMI) study.Circulation.1999;99:2626–2632.
- ,,,,,.Plasma glucose at hospital admission and previous metabolic control determine myocardial infarct size and survival in patients with and without type 2 diabetes: the Langendreer Myocardial Infarction and Blood Glucose in Diabetic Patients Assessment (LAMBDA).Diabetes Care.2005;28:2551–2553.
- ,,, et al.Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes.Circulation.2005;111:3078–3086.
- ,,, et al.Early predictors of in‐hospital death in infective endocarditis.Circulation.2004;109:1745–1749.
- .Relation between the duration of remission and hyperglycemia in induction chemotherapy for acute lymphocytic leukemia.Cancer.2004;100:1179–1185.
- ,,,,.Etiology and outcome of community‐acquired pneumonia in patients with diabetes mellitus.Chest.2005;128:3233–3239.
- ,,,.Perioperative glycemic control and the risk of infectious complications in a cohort of adults with diabetes.Diabetes Care.1999;22:1408–1414.
- ,,, et al.Early postoperative glucose control predicts nosocomial infection rate in diabetic patients.J Parenter Enteral Nutr.1998;22(2):77–81.
- ,,,,.The association of diabetes and glucose control with surgical‐site infections among cardiothoracic surgery patients.Infect Control Hosp Epidemiol.2001;22:607–612.
- ,,,,.Early post‐operative glucose levels are an independent risk factor for infection after peripheral vascular surgery. A retrospective study.Eur J Vasc Endovasc Surg.2004;5:520–525.
- ,,.Glucose control lowers the risk of wound infection in diabetics after open heart operations.Ann Thorac Surg.1997;63:356–61.
- ,,,.Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures.Ann Thorac Surg.1999;67:352–362.
- ,,, et al.Improving outcomes for diabetic patients undergoing vascular surgery.Diabetes Spectr.2005;18(1):53–60.
- ,,.Early postoperative outcome and medium‐term survival in 540 diabetic and 2239 nondiabetic patients undergoing coronary artery bypass grafting.Ann Thorac Surg.2002;74:712–719.
- ,,,,.Diabetes and coronary artery bypass surgery: an examination of perioperative glycemic control and outcomes.Diabetes Care.2003;26:1518–1524.
- ,,.Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland diabetic project.Endocr Pract.2004;10(suppl 2):21–33.
- ,,,,.Glucose‐insulin‐potassium solutions improve outcomes in diabetics who have coronary artery operations.Ann Thorac Surg.2000;70:145–150.
- ,,, et al.Intraoperative hyperglycemia and perioperative outcomes in cardiac surgery patients.Mayo Clin Proc.2005;80:862–866.
- ,,,.Postoperative hyperglycemia prolongs length of stay in diabetic CABG patients.Circulation. II2000;102(II):556 (abstract).
- .Reduction of hospital costs and length of stay by good control of blood glucose levels.Endocr Pract.2004;10(suppl 2):53–56.
- Tierney E: Data from the national hospital discharge survey database 2000.Centers for Disease Control and Prevention, Division of Diabetes translation,Atlanta, GA,2003.
- Moghissi E: Hospital management of diabetes: beyond the sliding scale.Clev Clin J Med.2004;71:801–808.
- ,,,,,.Hyperglycemia: an independent marker of in‐hospital mortality in patients with undiagnosed diabetes.J Clin Endocrinol Metab.2002;87:978–982.
- ,,,,Ratner RE: Unrecognized diabetes among hospitalized patients.Diabetes Care.1998;21:246–249.
- , for theDIGAMI study group.Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus.BMJ.1997;314:1512–1515.
- ,,, et al.Intensive insulin therapy in critically ill patients.N Engl J Med.2001;345:1359–1367.
- ,,, et al.Randomized trial of insulin‐glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year.J Am Coll Cardiol.1995;26:57–65.
- ,,,,,.Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.Circulation.2004;109:1497–1502.
- CREATE‐ECLA Trial Group Investigators.Effect of glucose‐insulin‐potassium infusion on mortality in patients with acute st‐segment elevation myocardial infarction: the CREATE‐ECLA randomized controlled trial.JAMA.2005;293:437–446.
- ,,, et al.Intensive insulin therapy in the medical ICU.N Engl J Med.2006;354:449–461.
- ,.Reduction of nosocomial infections in the surgical intensive‐care unit by strict glycemic control.Endocr Pract.2004;10(suppl 2):46–52.
- ,,, et al.Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting.J Thorac Cardiovasc Surg.2003;125:1007–1021.
- ,,,,,.Mortalilty in hospitalized patients with hypoglycemia and severe hyperglycemia.Mt Sinai J Med.1995;62:422–426.
- ,,,,,.Hyperglycemia: an independent marker of in‐hospital mortality in patients with undiagnosed diabetes.J Clin Endocrinol Metab.2002;87:978–982.
- ,,,.Glucose control and mortality in critically ill patients.JAMA.2003;290:2041–2047.
- .Effect of an intensive glucose management protocol on the mortality of critically ill adult patients.Mayo Clin Proc.2004:79:992–1000.
- ,,.Insulin therapy for critically ill hospitalized patients: a meta‐analysis of randomized controlled trials.Arch Intern Med.2004;164:2005–2011.
- ,,, et al.Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome.Stroke.2003;34:2208–2214.
- ,,,,.Stress hyperglycemia and prognosis of stroke in nodiabetic and diabetic patients: a systematic overview.Stroke.2001;32:2426–2432.
- ,,, et al.Admission glucose level and clinical outcomes in the NINDS rt‐PA Stroke Trial.Neurology.2002;59:669–674.
- .Effect of hyperglycemia on stroke outcomes.Endocr Pract.2004;10(suppl 2):34–39.
- ,,, et al.Predictors of hyperacute clinical worsening in ischemic stroke patients receiving thrombolytic therapy.Stroke.2004;35:1903–1907.
- ,.Hyperglycemia in acute stroke.Stroke.2004;35:363–364.
- ,,,,.Decreased mortality by normalizing blood glucose after acute ischemic stroke.Acad Emerg Med.2006;13:174–180.
- ,,.Blood glucose control after acute stroke: a retrospective study.Acad Emerg Med.2003;10:432.
- ,,,,.Relationship of early hyperglycemia to mortality in trauma patients.J Trauma.2004;56:1058–1062.
- ,,,,,.Admission hyperglycemia is predictive of outcome in critically ill trauma patients.J Trauma.2005;59:80–83.
- ,,, et al.Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke.Neurology.2002;59(1):67–71.
- ,,,,.Early peri‐operative glycaemic control and allograft rejection in patients with diabetes mellitus: a pilot study.Transplantation.2001;72:1321–1324.
- ,,,,.Early peri‐operative hyperglycaemia and renal allograft rejection in patients without diabetes.BMC Nephrol.2000;1:1.
- ,,,,.Protective effect of insulin on ischemic renal injury in diabetes mellitus.Kidney Int.2002;61:1383–1392.
- ,,,,,.Impaired glucose metabolism predicts mortality after a myocardial infarction.Int J Cardiol.2001;79 (2–3):207–214.
- ,,,.Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview.Lancet.2000;355:773–778.
- ,,, et al.A single serum glucose measurement predicts adverse outcomes across the whole range of acute coronary syndromes.Heart.2003;89:512–516.
- ,,,,,.Intensification of therapeutic approaches reduces mortality in diabetic patients with acute myocardial infarction: the Munich registry.Diabetes Care.2004;27:455–460.
- ,,, et al.Admission blood glucose level as risk indicator of death after myocardial infarction in patients with and without diabetes mellitus.Arch Intern Med.2004;164:982–988.
- ,,,.Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long‐term results from the diabetes and insulin‐glucose infusion in acute myocardial infarction (DIGAMI) study.Circulation.1999;99:2626–2632.
- ,,,,,.Plasma glucose at hospital admission and previous metabolic control determine myocardial infarct size and survival in patients with and without type 2 diabetes: the Langendreer Myocardial Infarction and Blood Glucose in Diabetic Patients Assessment (LAMBDA).Diabetes Care.2005;28:2551–2553.
- ,,, et al.Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes.Circulation.2005;111:3078–3086.
- ,,, et al.Early predictors of in‐hospital death in infective endocarditis.Circulation.2004;109:1745–1749.
- .Relation between the duration of remission and hyperglycemia in induction chemotherapy for acute lymphocytic leukemia.Cancer.2004;100:1179–1185.
- ,,,,.Etiology and outcome of community‐acquired pneumonia in patients with diabetes mellitus.Chest.2005;128:3233–3239.
- ,,,.Perioperative glycemic control and the risk of infectious complications in a cohort of adults with diabetes.Diabetes Care.1999;22:1408–1414.
- ,,, et al.Early postoperative glucose control predicts nosocomial infection rate in diabetic patients.J Parenter Enteral Nutr.1998;22(2):77–81.
- ,,,,.The association of diabetes and glucose control with surgical‐site infections among cardiothoracic surgery patients.Infect Control Hosp Epidemiol.2001;22:607–612.
- ,,,,.Early post‐operative glucose levels are an independent risk factor for infection after peripheral vascular surgery. A retrospective study.Eur J Vasc Endovasc Surg.2004;5:520–525.
- ,,.Glucose control lowers the risk of wound infection in diabetics after open heart operations.Ann Thorac Surg.1997;63:356–61.
- ,,,.Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures.Ann Thorac Surg.1999;67:352–362.
- ,,, et al.Improving outcomes for diabetic patients undergoing vascular surgery.Diabetes Spectr.2005;18(1):53–60.
- ,,.Early postoperative outcome and medium‐term survival in 540 diabetic and 2239 nondiabetic patients undergoing coronary artery bypass grafting.Ann Thorac Surg.2002;74:712–719.
- ,,,,.Diabetes and coronary artery bypass surgery: an examination of perioperative glycemic control and outcomes.Diabetes Care.2003;26:1518–1524.
- ,,.Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland diabetic project.Endocr Pract.2004;10(suppl 2):21–33.
- ,,,,.Glucose‐insulin‐potassium solutions improve outcomes in diabetics who have coronary artery operations.Ann Thorac Surg.2000;70:145–150.
- ,,, et al.Intraoperative hyperglycemia and perioperative outcomes in cardiac surgery patients.Mayo Clin Proc.2005;80:862–866.
- ,,,.Postoperative hyperglycemia prolongs length of stay in diabetic CABG patients.Circulation. II2000;102(II):556 (abstract).
- .Reduction of hospital costs and length of stay by good control of blood glucose levels.Endocr Pract.2004;10(suppl 2):53–56.
Benefits of Euglycemia
Until recently it had been argued that hospitalization was not the time in the life of a patient to insist on tight glycemic control. Hyperglycemia was understood to be a consequence of medical stress.1 It was well known that infection, sepsis, or other medical stress might exacerbate hyperglycemia or promote a diabetic crisis.25 Admittedly, the severity of hyperglycemia among patients who have diabetes was thought to predict the risk for hospitalization with infection as well as the outcome of the infectious condition.68 However, until recently strict glycemic control in the hospital was not strongly advocated because hypoglycemia might occur and might be directly and uniquely traceable to actions taken in the hospital.9, 10 Furthermore, the complications of diabetes were thought to be divided into acute metabolic emergencies and chronic tissue complications such as polyneuropathy, retinopathy, nephropathy, and macrovascular disease that would have evolved over a period longer than the duration of hospitalization, and the possibility that short‐term hyperglycemia might affect outcomes was considered unproven.
The purpose of this article is to define the specific populations, disorders, and hospital settings for which there now is strong evidence that short‐term glycemic control will affect the outcome of a course of hospital treatment.
PHYSIOLOGIC LINK BETWEEN HYPERGLYCEMIA AND ADVERSE OUTCOMES
Five years ago a caregiver would not have been likely to think of glycemic control as a contributing factor when considering specific complex problems such as pump failure or arrhythmia after cardiac surgery, long‐term mortality after myocardial infarction, acute renal failure, the need for transfusion during treatment of a complicated surgical illness, or prolonged dependence on a ventilator in the surgical ICU. Although it now known that these and other complications are linked to hospital hyperglycemia, the mechanisms of harm are several steps removed from the hyperglycemia itself. The causes of these adverse outcomes are multifactorial. The causal dependence of the injury on hyperglycemia is not easy to see. In fact, it required randomized prospectively designed trials to convincingly demonstrate the contributory role of hyperglycemia to these and other adverse outcomes.
Now that this link has been convincingly demonstrated, there is intense interest in discovering the probable mechanisms by which control of hyperglycemia and specifically the use of insulin might improve outcomes.1114 Mortality, predominantly sepsis related, was the primary outcome for which the Leuven, Belgium, report of 2001 on the surgical ICU showed improvement.15 Simplistically, in seeking a mechanism of benefit with respect to sepsis, it might be argued that if gross hyperglycemia were prevented in patients with surgical wounds, improvement of host defenses against infective organisms might be expected.1622 However, additional mechanisms of protection probably should be invoked, including those by which glycemic control and specifically insulin therapy affect endothelial function and the coagulation pathway, thus improving the ability of a patient to withstand and recover from sepsis. Insulin promotes beneficial nitric oxide synthase activation (e‐NOS) in capillary endothelium.2326 In patients with prolonged critical illness, intensive insulin therapy lowers ICAM‐1 levels, reflecting reduced endothelial activation. Whereas e‐NOS exerts a beneficial endothelial effect, hepatic iNOS activation is harmful. One proposed mechanism of benefit from adequate insulin therapy is suppression of excessive hepatic iNOS‐induced release of circulating NO, which might contribute to endothelial dysfunction, organ failure, and death.27
Additional proposed mechanisms of hyperglycemia‐induced harm to hospitalized patients, some potentially specifically reduced by insulin therapy, resemble those discussed in relation to macrovascular disease and include activation of inflammatory cytokines, matrix metalloproteinases, and adhesion molecules, and the adverse arrhythmogenic effects of elevated circulating nonesterified fatty acids (Figure 1).2834
CRITICAL WINDOW OF TIME
The results of several retrospectively or prospectively conducted single‐institution observational studies suggest there is a critical window of time within which clinicians must get it right, when attempting glycemic control or else jeopardize therapeutic goals, such as duration of remission in treatment of acute lymphocytic leukemia35 or avoidance of acute rejection in renal allograft surgery.36 Additionally, delayed risk of infection appears to be linked to previous glycemic control during specific early time frames surrounding surgery, renal transplantation, admission for trauma, and induction chemotherapy for leukemia (Table 1).3541 For patients who have diabetes, the potential to reduce the consequences of infections through intensified glycemic control probably begins prior to admission and in the hospital has still not been fully realized.4244
| Patients | Ascertainment of hyperglycemia | Delayed events among patients with early hyperglycemia |
|---|---|---|
| 100 postoperative uninfected diabetic patients undergoing elective surgery, monitored prospectively37 | First postoperative day | Postoperative nosocomial infection rate within 14 days was 2.7 times higher for patients having at least one BG > 220 mg/dL (33.3% vs. 11.5%). |
| 990 historical controls and 595 patients in the interventional group of postoperative cardiac diabetic patients40 | First 2 postoperative days | Incidence of deep sternal wound infection was reduced from 2.4% to 1.5% (P < 0.02) after introduction of protocol to maintain mean BG < 200 mg/dL. |
| 423 renal allograft recipients receiving their first cadaveric transplant36 | First 100 hours; first day. | A mean of 10.8 2.3 days after transplantation, 70% of patients developed postoperative infection, and after a mean of 7.7 2.6 days, 40% developed acute rejection. Every patient with mean BG over 200 mg/dL during the first 100 hours developed postoperative infection. On the first postoperative day the mean BG had been 248.4 mg/dL among those developing infection and 167.4 mg/dL among those without infection (P < .001), and the mean BG had been 270 mmol/L among those developing rejection and 194 mmol/L among those without rejection. |
| 516 trauma patients admitted to the ICU38 | Either of first 2 hospital days | Hyperglycemia 200 mg/dL was associated with a higher infection rate (32% vs. 22%, P = .04) and with greater mortality (34% vs. 13%, P < .0001) |
| 275 patients having lower‐extremity peripheral vascular surgery39 | First 48 hours | Postoperative infections within 30 days were 5.1 times more frequent in the top quartile for BG versus the lowest quartile (confidence interval 1.6‐17.1, P = .007). |
| 278 adult patients receiving induction chemotherapy for acute lymphocytic leukemia35 | First 30 days | Hyperglycemia defined as 2 BG 200 mg/dL was associated with a greater likelihood of sepsis (16.5% vs. 8.0%, P = .03) or any complicated infection (38.8% vs. 25.1%, P = .016), shorter duration of complete remission (24 vs. 52 months), and with shorter median survival (29 vs. 88 months, P = .001). |
KEY STUDIES SHOWING CLINICAL BENEFIT OF TIGHT GLYCEMIC CONTROL
A summary of several key studies that demonstrated the clinical benefit of tight glycemic control is shown in Table 2. These studies successfully separated the intensively and conventionally managed study groups according blood glucose. Although trials using glucose‐insulin‐potassium infusions (GIK) such that blood glucose was lowered have shown benefit for patients who have had myocardial infarctions4547 or cardiac surgery,48 not all GIK studies have yielded positive results. The negative results of the CREATE‐ECLA study suggest that GIK therapy per se is not beneficial unless it reduces blood glucose.49 In the setting of acute myocardial infarction, the DIGAMI 2 trial and the HI‐5 trials failed to achieve the intended separation between treatment groups.50, 51 It has been speculated that if insulin is delivered so as to not achieve normoglycemia, then hyperinsulinemia in the presence of hyperglycemia actually may be proinflammatory.52
| Population and/or setting and patients | Study design and/or intervention | Principal findings |
|---|---|---|
| Patients with diabetes mellitus and with hyperglycemia > 11 mmol/L or similar hyperglycemia without known diabetes who had had acute myocardial within the preceding 24 hours.4547 There were 620 patients, of whom 15 of the controls and 10 patients in the intensive group had no prior diagnosis of diabetes. | Prospective, randomized, controlled clinical trial. Controls received standard treatment. Treatment group received infusion of glucose‐insulin for at least 24 hours, followed by multiple injections of subcutaneous insulin for at least 3 months. | Overall mortality after 1 year was l9% in the insulin group compared to 26% among controls (P < .05). The most frequent cause of death of all patients was congestive heart failure. The benefit continued for at least 3.5 years, with an absolute reduction in mortality of 11%. |
| Diabetic cardiac surgery population.40, 5557 To date, 5510 cardiac surgery patients who were either admitted or discharged with the diagnosis of diabetes have been studied. | Prospective nonrandomized study of the effects of hyperglycemia and its pharmacologic reduction with intensive intravenous insulin regimens on outcomes. | The 3‐day average of perioperative BG (3‐BG) correlated with mortality (P < .0001, odds ratio 2.0 per 50 mg/dL increase in 3‐BG). Continuous intravenous insulin infusion independently reduced risk of death 60% (RR = 0.4, P < .001). Length of stay in the CABG population increased by 1 day for every increase of 50 mg/dL in 3‐BG. |
| Critically ill surgical patients receiving mechanical ventilation. Overall, 13% of 1548 participants had previously diagnosed diabetes. | Prospective, randomized, controlled clinical trial. Intravenous insulin infusion targeting BG 80‐110 mg/dL was initiated in the intensive group for BG > 110 mg/dL. Intravenous insulin infusion targeting BG 180‐200 was initiated in the conventional group for BG > 215 mg/dL. A whole‐blood glucose method using a gas analyzer was employed to determine arterial blood glucose. | In the group assigned to intensive insulin therapy mortality was reduced during intensive care from 8.0% with conventional treatment to 4.6% (P < .04), or a risk reduction of 42%. In the group remaining in the ICU for more than 5 days, mortality was reduced from 20.2% with conventional treatment to 10.6% with intensive insulin therapy; P = .005. The intensive group experienced reductions in overall in‐hospital mortality of 34%, in bloodstream infections of 46%, and in acute renal failure requiring dialysis or hemofiltration of 41%. Also reduced were the need for red‐cell transfusions, critical‐illness neuropathy, duration of mechanical ventilation, and length of stay in the ICU. |
| Critically ill medical patients. The intention to treat group included 1200 participants, of whom 16.9% had a history of diabetes.54 | Randomized controlled clinical trial, as above. | In the intensive group, in‐hospital mortality was not significantly reduced, and among the 433 who stayed in the ICU for less than 3 days, mortality was actually higher. However, in the intention‐to‐treat group there was reduction in newly acquired kidney injury, prolonged mechanical ventilation, and length of stay in the ICU and in the hospital. Among the 767 patients who stayed in the ICU for 3 or more days, intensive insulin therapy reduced in‐hospital mortality from 52.5% to 43.0%. |
| Patients within 24 hours of having an acute stroke and who had poststroke hyperglycemia. The results of the first 452 patients recruited to the GIST‐UK study showed that 15.3% had previously recognized diabetes.62 | Randomized controlled clinical trial. The intensive group received glucose‐potassium‐insulin (GKI) infusion, and the conventional group received saline infusion. | Although mean glucose declined in both groups, the GKI infusion safely achieved separation of groups by blood glucose. Outcomes are pending. |
The findings of the negative intensive insulin studies do not offset the evidence favoring glycemic control, derived from studies that actually achieved the lowering of blood glucose in the intensive groups, such as the successful prospectively designed trials in myocardial infarction or surgical or medical intensive care units15, 45, 47, 53, 54 and the long‐running, large, prospectively monitored Portland series utilizing insulin infusion for cardiac surgery,40, 5557 which have demonstrated the beneficial effects of euglycemia on mortality and morbidity, or the findings of Krinsley, reported elsewhere in this issue.58, 59 The well‐recognized correlation between outcomes of acute stroke and poststroke hyperglycemia has led to the design of a multicenter trial of glucose‐insulin‐potassium infusion for stroke, in which separation of groups by blood glucose has been achieved.6062 The success of GIK therapy in controlling hyperglycemia depends in part on the particular formulation of the infusion as it matches patient needs, and it is probable that insulin infusion following stroke is capable of safely achieving even tighter glycemic control than GIK.63 Intravenous insulin infusion therapy is more difficult to conduct than GIK therapy. However, because of concern about the proinflammatory and prothrombotic effects of hyperglycemia and recognition of the occasional failure of GIK infusions to control hyperglycemia and of the anti‐inflammatory, antithrombotic, and vasodilatory actions of insulin, there have been calls for additional trials of insulin infusions (as opposed to glucose‐insulin infusions) for both acute myocardial infarction and stroke.52, 64
HYPOGLYCEMIA
Serious or fatal sequelae of hypoglycemia are the principal safety risks in intensive insulin management.9, 65 Case ascertainment cannot be assured by glucose averaging methods but instead requires a method of searching for isolated episodes of hypoglycemia.10 One of the most dreaded consequences of nonfatal hypoglycemia is permanent impairment of intellectual function. Because many euglycemic medically ill patients experience alteration of sensorium while acutely ill, there is a risk that the consequences of an actual episode of severe hypoglycemia will be ascribed to other comorbidities, overlooking or misattributing the altered cognitive function that may persist at discharge to causes other than the obvious iatrogenic one. Because there is an increased risk of hypoglycemia during intensive insulin therapy, controversy has arisen over glycemic targets, especially among critically ill nonsurgical patients.54, 6669
On the other hand, the consequences of hypoglycemia during intensive intravenous insulin therapy in a surgical ICU were said to be negligible.15 In hospitalized elderly patients, hypoglycemia in association with increased mortality risk may not be an independent predictor.70 In the critical care unit, predictors of hypoglycemia are identifiable after the introduction of strict glycemic control that include not only insulin therapy but also CVVH treatment with bicarbonate substitution fluid, discontinuation of nutrition without insulin adjustment, prior diagnosis of diabetes mellitus, sepsis, and the need for inotropic or vasopressor drugs.71 A prudent policy for the future would be not only to treat hypoglycemia promptly when it does occur, with attention to subsequent monitoring to avoid relapse or recurrence, but also to actively introduce strategies for predicting the risk of hypoglycemia and preventing it, especially when high risk is identified.10 The fear of hypoglycemia should not paralyze efforts to achieve better glycemic control in hospitalized patients.
UNANSWERED QUESTIONS AND VISION FOR THE FUTURE
On general wards, 38% of admitted patients may have hyperglycemia.72 As shown in the Leuven, Belgium, study, to achieve the target BG of less than 110 mg/dL in the intensive group in the surgical critical care unit, it was necessary to administer intravenous insulin infusion to essentially all patients. In a study that utilized continuous glucose monitoring, normoglycemia in patients in the intensive care unit was achieved as little as 22% of the time.73
An actively debated subject is how best to assess hospital performance in glycemic control (glucometrics). Hospitals need to show satisfactory control of variability between patients and within the treatment course of individual patients. That is, it is not sufficient to be satisfied with reasonable results of average blood glucose, using blood glucose as the unit of observation (where n is the number of blood glucose determinations). Alternatives are to use patient day or individual patient as a unit of observation (where n is the number of patient days and the number of patients, respectively). Time‐weighting methods are cumbersome but increase the validity of the averaging method used. When the patient is the unit of observation, possible measures include a per‐patient blood glucose average, percentage of blood glucose measurements with certain ranges, time spent within certain blood glucose ranges, or area under the curve of blood glucose versus time. Caveats about glucometrics pertain to both intravenous insulin infusion and also subcutaneous insulin management.74
Although awaiting additional evidence, diabetes experts have widely accepted the proposition that hospitals should focus on prevention of hyperglycemia as an important patient safety factor.75 Although the target range for glycemic control remains controversial, many students of the subject have endorsed the recommendations mentioned in the lead article in this issue, with the understanding that these criteria were developed from the results of the Leuven, Belgium, study, in which a whole blood glucose analyzer was used for measurement, and that the method of measurement of blood glucose must be considered in interpreting applicability of the target range at individual hospitals, many of which use plasma‐correlated methods yielding higher results. However, in new settings and for medical conditions that have not yet been rigorously evaluated by clinical trials, it is an unanswered question whether intensification of glycemic control can be achieved safely outside the critical care unit and, if so, what type of insulin therapy should be used and for what conditions the benefits would outweigh the risks and justify the costs.
Most inpatient management probably will continue to be conducted using subcutaneous injection therapy,7682 designed to match carbohydrate exposure through the appropriate use of analogs or conventional insulin products. One argument for the use of insulin analogs in the hospital, using basal‐prandial‐correction therapy, is the probability of reducing hypoglycemia and getting closer to target range control among patients who are eating but who are at risk for abrupt suspension of meals. Aggressive subcutaneous management strategies are likely to be most effective when standardized protocols, order sets, and informative computerized order entry systems gain widespread hospital acceptance.
If the importance of gaining glycemic control is highly time dependent and if hyperglycemia is uncontrolled, then a strong argument can be made for routine use of intravenous insulin infusion. For appropriately selected patients, intravenous insulin infusion is cost effective,83, 84 and its use can be extended to appropriate patients outside the critical care unit.8587 Many hospitals have protocols for intravenous insulin but use them only sporadically. For patients who already are in the intensive care setting, it is imperative to develop policies that require introduction of intravenous insulin infusion at a given glycemic threshold. On general wards that lack sufficient staffing to conduct intravenous insulin therapy, it is appropriate either to transfer candidate patients to a ward that has adequate staffing when medical condition requires improved control or to develop policies and procedures that will extend the use of intravenous insulin infusion to general wards. In the future, new technologies can be envisioned that will unburden nursing staff, making intravenous insulin infusion realizable as the treatment of choice for hemodynamically stable patients in most hospital settings. These technologies will include continuous monitoring of blood glucose, dose‐defining algorithms, and the eventual development of a fully automated closed‐loop system of monitoring and delivery that might automatically match insulin delivery to carbohydrate exposure and patient insulin sensitivity.8893
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- ,,.Insulin treatment improves the systemic inflammatory reaction to severe trauma.Ann Surg.2004;239:553–560.
- ,,, et al.Anti‐inflammatory and profibrinolytic effect of insulin in acute ST‐segment‐elevation myocardial infarction.Circulation.2004;109:849–854.
- .Relation between the duration of remission and hyperglycemia in induction chemotherapy for acute lymphocytic leukemia.Cancer.2004;100:1179–1185.
- ,,,,.Early peri‐operative glycaemic control and allograft rejection in patients with diabetes mellitus: a pilot study.Transplantation.2001;72:1321–1324.
- ,,, et al.Early postoperative glucose control predicts nosocomial infection rate in diabetic patients.J Parenter Enteral Nutr.1998;22(2):77–81.
- ,,,,.Relationship of early hyperglycemia to mortality in trauma patients.J Trauma.2004;56:1058–1062.
- ,,,,.Early post‐operative glucose levels are an independent risk factor for infection after peripheral vascular surgery. A retrospective study.Eur J Vasc Endovasc Surg.2004;5:520–525.
- ,,,.Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures.Ann Thorac Surg.1999;67:352–362.
- ,.Effects on outcome of in‐hospital transition from intravenous insulin infusion to subcutaneous therapy.Am J Cardiol.2006;98:557–564.
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- .Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus.DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group.BMJ.1997;314:1512–1515.
- ,,,,,.Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.Circulation.2004;109:1497–1502.
- .Effect of Glucose‐Insulin‐Potassium Infusion on Mortality in Patients With Acute ST‐Segment Elevation Myocardial Infarction: The CREATE‐ECLA Randomized Controlled Trial.JAMA.2005;293:437–446.
- ,,, et al.Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity.Eur Heart J.2005;26:650–661.
- ,,.The Hyperglycemia: Intensive Insulin Infusion In Infarction (HI‐5) Study: A randomized controlled trial of insulin infusion therapy for myocardial infarction.Diabetes Care.2006;29:765–770.
- .Inpatient diabetes: review of data from the cardiac care unit.Endocr Pract.2006;12(suppl 3):27–34.
- ,.Reduction of nosocomial infections in the surgical intensive‐care unit by strict glycemic control.Endocr Pract.2004;10(suppl 2):46–52.
- ,,, et al.Intensive insulin therapy in the medical ICU.N Engl J Med.2006;354:449–461.
- ,,.Glucose control lowers the risk of wound infection in diabetics after open heart operations.Ann Thorac Surg.1997;63:356–361.
- ,,, et al.Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting.J Thorac Cardiovasc Surg.2003;125:1007–1021.
- ,.Clinical effects of hyperglycemia in the cardiac surgery population: the Portland diabetic project.Endocr Pract.2006;12(suppl 3):22–26.
- .Effect of an intensive glucose management protocol on the mortality of critically ill adult patients.Mayo Clin Proc.2004;79:992–1000.
- .Decreased mortality of critically ill patients with the use of an intensive glycemic management protocol.Mayo Clin Proc.2003;78:1471–1478.
- ,,, et al.Admission glucose level and clinical outcomes in the NINDS rt‐PA Stroke. Trial.Neurology.2002;59:669–74.
- ,,,,,.Glucose potassium insulin infusions in the treatment of acute stroke patients with mild to moderate hyperglycemia: the Glucose Insulin in Stroke. Trial (GIST).Stroke.1999;30:793–799.
- ,,,.Poststroke hyperglycemia: natural history and immediate management.Stroke.2004;35(1):122–126.
- ,,,.IV insulin during acute cerebral infarction in diabetic patients.Neurology.2004;62:1441–1442.
- ,,,.Hyperglycemia, insulin, and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy.Stroke.2006;37(1):267–273.
- ,,.Hypoglycemia and cardiac arrest in a critically ill patient on strict glycemic control.Anesth Analg.2006;102:549–551.
- ,,.Strict glucose control in the critically ill.Br Med J.2006;332:865–866.
- .Intensive Insulin in Intensive Care.N Engl J Med.2006;354:516–518.
- ,.Counterpoint: Inpatient glucose management: a premature call to arms?Diabetes Care.2005;28:976–979.
- ,,,.Glucose control and mortality in critically ill patients.JAMA.2003;290:2041–2047.
- ,,, et al.Hypoglycemia as a predictor of mortality in hospitalized elderly patients.Arch Intern Med.2003;163:1825–1829.
- ,,, et al.Predisposing factors for hypoglycemia in the intensive care unit.Crit Care Med.2006;34:96–101.
- ,,,,,.Hyperglycemia: an independent marker of in‐hospital mortality in patients with undiagnosed diabetes.J Clin Endocrinol Metab.2002;87:978–982.
- ,,,.Intensive insulin therapy in the intensive care unit: assessment by continuous glucose monitoring.Diabetes Care.2006;29:1750–1756.
- ,,,.No patient left behind: evaluation and design of intravenous insulin infusion algorithms.Endocr Pract.2006;12(suppl 3):72–78.
- ,,, et al.Management of diabetes and hyperglycemia in hospitals.Diabetes Care.2004;27:553–591.
- ,,,.Eliminating Inpatient Sliding‐Scale Insulin: A reeducation project with medical house staff.Diabetes Care.2005;28:1008–1011.
- ,,.70/30 Insulin algorithm versus sliding scale insulin.Ann Pharmacother.2005;39:1606–1609.
- ,.Hospital management of hyperglycemia.Clin Diabetes.2004;22(2):81–88.
- ,.Subcutaneous insulin therapy in the hospital setting: issues, concerns, and implementation.Endocr Pract.2004;10(suppl 2):81–88.
- ,,,,.Hyperglycemia in the hospital.Diabetes Spectr.2005;18(1):20–27.
- .Insulin Analogues.N Engl J Med.2005;352:174–183.
- .Insulin management of diabetic patients on general medical and surgical floors.Endocr Pract.2006;12(suppl 3):86–90.
- ,,, et al.Improved perioperative glycemic control by continuous insulin infusion under supervision of an endocrinologist does not increase costs in patients with diabetes.Endocr Pract.2004;10(2):112–118.
- ,,.Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland Diabetic Project.Endocr Pract.2004;10(suppl 2):21–33.
- ,,,.New insulin infusion protocol improves blood glucose control in hospitalized patients without increasing hypoglycemia.J Qual Patient Saf.2005;31:141–147.
- ,,,,.Optimizing hospital use of intravenous insulin therapy: improved management of hyperglycemia and error reduction with a new nomogram.Endocr Pract.2005;11:240–253.
- ,,,,.Implementation of a new intravenous insulin method on intermediate‐care units in hospitalized patients.Diabetes Educ.2005;31:818–823.
- ,,.Clinical results of an updated insulin infusion protocol in critically ill patients.Diabetes Spectr.2005;18(3):188–191.
- ,,.Glucommander: A computer‐directed intravenous insulin system shown to be safe, simple, and effective in 120,618 h of operation.Diabetes Care.2005;28:2418–2423.
- ,,, et al.Improving hyperglycemia management in the intensive care unit: preliminary report of a nurse‐driven quality improvement project using a redesigned insulin infusion algorithm.Diabetes Educ.2006;32:394–403.
- ,,, et al.Performance of a dose‐defining insulin infusion protocol among trauma service ICU admissions.Diabetes Technol Ther.2006;8:476–488.
- ,,, et al.A simple insulin‐nutrition protocol for tight glycemic control in critical illness: development and protocol comparison.Diabetes Technol Ther.2006;8:191–206.
- ,,, et al.Evaluation of the impact of chiropodist care in the secondary prevention of foot ulcerations in diabetic subjects.Diabetes Care.2003;26:1691–1695.
Until recently it had been argued that hospitalization was not the time in the life of a patient to insist on tight glycemic control. Hyperglycemia was understood to be a consequence of medical stress.1 It was well known that infection, sepsis, or other medical stress might exacerbate hyperglycemia or promote a diabetic crisis.25 Admittedly, the severity of hyperglycemia among patients who have diabetes was thought to predict the risk for hospitalization with infection as well as the outcome of the infectious condition.68 However, until recently strict glycemic control in the hospital was not strongly advocated because hypoglycemia might occur and might be directly and uniquely traceable to actions taken in the hospital.9, 10 Furthermore, the complications of diabetes were thought to be divided into acute metabolic emergencies and chronic tissue complications such as polyneuropathy, retinopathy, nephropathy, and macrovascular disease that would have evolved over a period longer than the duration of hospitalization, and the possibility that short‐term hyperglycemia might affect outcomes was considered unproven.
The purpose of this article is to define the specific populations, disorders, and hospital settings for which there now is strong evidence that short‐term glycemic control will affect the outcome of a course of hospital treatment.
PHYSIOLOGIC LINK BETWEEN HYPERGLYCEMIA AND ADVERSE OUTCOMES
Five years ago a caregiver would not have been likely to think of glycemic control as a contributing factor when considering specific complex problems such as pump failure or arrhythmia after cardiac surgery, long‐term mortality after myocardial infarction, acute renal failure, the need for transfusion during treatment of a complicated surgical illness, or prolonged dependence on a ventilator in the surgical ICU. Although it now known that these and other complications are linked to hospital hyperglycemia, the mechanisms of harm are several steps removed from the hyperglycemia itself. The causes of these adverse outcomes are multifactorial. The causal dependence of the injury on hyperglycemia is not easy to see. In fact, it required randomized prospectively designed trials to convincingly demonstrate the contributory role of hyperglycemia to these and other adverse outcomes.
Now that this link has been convincingly demonstrated, there is intense interest in discovering the probable mechanisms by which control of hyperglycemia and specifically the use of insulin might improve outcomes.1114 Mortality, predominantly sepsis related, was the primary outcome for which the Leuven, Belgium, report of 2001 on the surgical ICU showed improvement.15 Simplistically, in seeking a mechanism of benefit with respect to sepsis, it might be argued that if gross hyperglycemia were prevented in patients with surgical wounds, improvement of host defenses against infective organisms might be expected.1622 However, additional mechanisms of protection probably should be invoked, including those by which glycemic control and specifically insulin therapy affect endothelial function and the coagulation pathway, thus improving the ability of a patient to withstand and recover from sepsis. Insulin promotes beneficial nitric oxide synthase activation (e‐NOS) in capillary endothelium.2326 In patients with prolonged critical illness, intensive insulin therapy lowers ICAM‐1 levels, reflecting reduced endothelial activation. Whereas e‐NOS exerts a beneficial endothelial effect, hepatic iNOS activation is harmful. One proposed mechanism of benefit from adequate insulin therapy is suppression of excessive hepatic iNOS‐induced release of circulating NO, which might contribute to endothelial dysfunction, organ failure, and death.27
Additional proposed mechanisms of hyperglycemia‐induced harm to hospitalized patients, some potentially specifically reduced by insulin therapy, resemble those discussed in relation to macrovascular disease and include activation of inflammatory cytokines, matrix metalloproteinases, and adhesion molecules, and the adverse arrhythmogenic effects of elevated circulating nonesterified fatty acids (Figure 1).2834
CRITICAL WINDOW OF TIME
The results of several retrospectively or prospectively conducted single‐institution observational studies suggest there is a critical window of time within which clinicians must get it right, when attempting glycemic control or else jeopardize therapeutic goals, such as duration of remission in treatment of acute lymphocytic leukemia35 or avoidance of acute rejection in renal allograft surgery.36 Additionally, delayed risk of infection appears to be linked to previous glycemic control during specific early time frames surrounding surgery, renal transplantation, admission for trauma, and induction chemotherapy for leukemia (Table 1).3541 For patients who have diabetes, the potential to reduce the consequences of infections through intensified glycemic control probably begins prior to admission and in the hospital has still not been fully realized.4244
| Patients | Ascertainment of hyperglycemia | Delayed events among patients with early hyperglycemia |
|---|---|---|
| 100 postoperative uninfected diabetic patients undergoing elective surgery, monitored prospectively37 | First postoperative day | Postoperative nosocomial infection rate within 14 days was 2.7 times higher for patients having at least one BG > 220 mg/dL (33.3% vs. 11.5%). |
| 990 historical controls and 595 patients in the interventional group of postoperative cardiac diabetic patients40 | First 2 postoperative days | Incidence of deep sternal wound infection was reduced from 2.4% to 1.5% (P < 0.02) after introduction of protocol to maintain mean BG < 200 mg/dL. |
| 423 renal allograft recipients receiving their first cadaveric transplant36 | First 100 hours; first day. | A mean of 10.8 2.3 days after transplantation, 70% of patients developed postoperative infection, and after a mean of 7.7 2.6 days, 40% developed acute rejection. Every patient with mean BG over 200 mg/dL during the first 100 hours developed postoperative infection. On the first postoperative day the mean BG had been 248.4 mg/dL among those developing infection and 167.4 mg/dL among those without infection (P < .001), and the mean BG had been 270 mmol/L among those developing rejection and 194 mmol/L among those without rejection. |
| 516 trauma patients admitted to the ICU38 | Either of first 2 hospital days | Hyperglycemia 200 mg/dL was associated with a higher infection rate (32% vs. 22%, P = .04) and with greater mortality (34% vs. 13%, P < .0001) |
| 275 patients having lower‐extremity peripheral vascular surgery39 | First 48 hours | Postoperative infections within 30 days were 5.1 times more frequent in the top quartile for BG versus the lowest quartile (confidence interval 1.6‐17.1, P = .007). |
| 278 adult patients receiving induction chemotherapy for acute lymphocytic leukemia35 | First 30 days | Hyperglycemia defined as 2 BG 200 mg/dL was associated with a greater likelihood of sepsis (16.5% vs. 8.0%, P = .03) or any complicated infection (38.8% vs. 25.1%, P = .016), shorter duration of complete remission (24 vs. 52 months), and with shorter median survival (29 vs. 88 months, P = .001). |
KEY STUDIES SHOWING CLINICAL BENEFIT OF TIGHT GLYCEMIC CONTROL
A summary of several key studies that demonstrated the clinical benefit of tight glycemic control is shown in Table 2. These studies successfully separated the intensively and conventionally managed study groups according blood glucose. Although trials using glucose‐insulin‐potassium infusions (GIK) such that blood glucose was lowered have shown benefit for patients who have had myocardial infarctions4547 or cardiac surgery,48 not all GIK studies have yielded positive results. The negative results of the CREATE‐ECLA study suggest that GIK therapy per se is not beneficial unless it reduces blood glucose.49 In the setting of acute myocardial infarction, the DIGAMI 2 trial and the HI‐5 trials failed to achieve the intended separation between treatment groups.50, 51 It has been speculated that if insulin is delivered so as to not achieve normoglycemia, then hyperinsulinemia in the presence of hyperglycemia actually may be proinflammatory.52
| Population and/or setting and patients | Study design and/or intervention | Principal findings |
|---|---|---|
| Patients with diabetes mellitus and with hyperglycemia > 11 mmol/L or similar hyperglycemia without known diabetes who had had acute myocardial within the preceding 24 hours.4547 There were 620 patients, of whom 15 of the controls and 10 patients in the intensive group had no prior diagnosis of diabetes. | Prospective, randomized, controlled clinical trial. Controls received standard treatment. Treatment group received infusion of glucose‐insulin for at least 24 hours, followed by multiple injections of subcutaneous insulin for at least 3 months. | Overall mortality after 1 year was l9% in the insulin group compared to 26% among controls (P < .05). The most frequent cause of death of all patients was congestive heart failure. The benefit continued for at least 3.5 years, with an absolute reduction in mortality of 11%. |
| Diabetic cardiac surgery population.40, 5557 To date, 5510 cardiac surgery patients who were either admitted or discharged with the diagnosis of diabetes have been studied. | Prospective nonrandomized study of the effects of hyperglycemia and its pharmacologic reduction with intensive intravenous insulin regimens on outcomes. | The 3‐day average of perioperative BG (3‐BG) correlated with mortality (P < .0001, odds ratio 2.0 per 50 mg/dL increase in 3‐BG). Continuous intravenous insulin infusion independently reduced risk of death 60% (RR = 0.4, P < .001). Length of stay in the CABG population increased by 1 day for every increase of 50 mg/dL in 3‐BG. |
| Critically ill surgical patients receiving mechanical ventilation. Overall, 13% of 1548 participants had previously diagnosed diabetes. | Prospective, randomized, controlled clinical trial. Intravenous insulin infusion targeting BG 80‐110 mg/dL was initiated in the intensive group for BG > 110 mg/dL. Intravenous insulin infusion targeting BG 180‐200 was initiated in the conventional group for BG > 215 mg/dL. A whole‐blood glucose method using a gas analyzer was employed to determine arterial blood glucose. | In the group assigned to intensive insulin therapy mortality was reduced during intensive care from 8.0% with conventional treatment to 4.6% (P < .04), or a risk reduction of 42%. In the group remaining in the ICU for more than 5 days, mortality was reduced from 20.2% with conventional treatment to 10.6% with intensive insulin therapy; P = .005. The intensive group experienced reductions in overall in‐hospital mortality of 34%, in bloodstream infections of 46%, and in acute renal failure requiring dialysis or hemofiltration of 41%. Also reduced were the need for red‐cell transfusions, critical‐illness neuropathy, duration of mechanical ventilation, and length of stay in the ICU. |
| Critically ill medical patients. The intention to treat group included 1200 participants, of whom 16.9% had a history of diabetes.54 | Randomized controlled clinical trial, as above. | In the intensive group, in‐hospital mortality was not significantly reduced, and among the 433 who stayed in the ICU for less than 3 days, mortality was actually higher. However, in the intention‐to‐treat group there was reduction in newly acquired kidney injury, prolonged mechanical ventilation, and length of stay in the ICU and in the hospital. Among the 767 patients who stayed in the ICU for 3 or more days, intensive insulin therapy reduced in‐hospital mortality from 52.5% to 43.0%. |
| Patients within 24 hours of having an acute stroke and who had poststroke hyperglycemia. The results of the first 452 patients recruited to the GIST‐UK study showed that 15.3% had previously recognized diabetes.62 | Randomized controlled clinical trial. The intensive group received glucose‐potassium‐insulin (GKI) infusion, and the conventional group received saline infusion. | Although mean glucose declined in both groups, the GKI infusion safely achieved separation of groups by blood glucose. Outcomes are pending. |
The findings of the negative intensive insulin studies do not offset the evidence favoring glycemic control, derived from studies that actually achieved the lowering of blood glucose in the intensive groups, such as the successful prospectively designed trials in myocardial infarction or surgical or medical intensive care units15, 45, 47, 53, 54 and the long‐running, large, prospectively monitored Portland series utilizing insulin infusion for cardiac surgery,40, 5557 which have demonstrated the beneficial effects of euglycemia on mortality and morbidity, or the findings of Krinsley, reported elsewhere in this issue.58, 59 The well‐recognized correlation between outcomes of acute stroke and poststroke hyperglycemia has led to the design of a multicenter trial of glucose‐insulin‐potassium infusion for stroke, in which separation of groups by blood glucose has been achieved.6062 The success of GIK therapy in controlling hyperglycemia depends in part on the particular formulation of the infusion as it matches patient needs, and it is probable that insulin infusion following stroke is capable of safely achieving even tighter glycemic control than GIK.63 Intravenous insulin infusion therapy is more difficult to conduct than GIK therapy. However, because of concern about the proinflammatory and prothrombotic effects of hyperglycemia and recognition of the occasional failure of GIK infusions to control hyperglycemia and of the anti‐inflammatory, antithrombotic, and vasodilatory actions of insulin, there have been calls for additional trials of insulin infusions (as opposed to glucose‐insulin infusions) for both acute myocardial infarction and stroke.52, 64
HYPOGLYCEMIA
Serious or fatal sequelae of hypoglycemia are the principal safety risks in intensive insulin management.9, 65 Case ascertainment cannot be assured by glucose averaging methods but instead requires a method of searching for isolated episodes of hypoglycemia.10 One of the most dreaded consequences of nonfatal hypoglycemia is permanent impairment of intellectual function. Because many euglycemic medically ill patients experience alteration of sensorium while acutely ill, there is a risk that the consequences of an actual episode of severe hypoglycemia will be ascribed to other comorbidities, overlooking or misattributing the altered cognitive function that may persist at discharge to causes other than the obvious iatrogenic one. Because there is an increased risk of hypoglycemia during intensive insulin therapy, controversy has arisen over glycemic targets, especially among critically ill nonsurgical patients.54, 6669
On the other hand, the consequences of hypoglycemia during intensive intravenous insulin therapy in a surgical ICU were said to be negligible.15 In hospitalized elderly patients, hypoglycemia in association with increased mortality risk may not be an independent predictor.70 In the critical care unit, predictors of hypoglycemia are identifiable after the introduction of strict glycemic control that include not only insulin therapy but also CVVH treatment with bicarbonate substitution fluid, discontinuation of nutrition without insulin adjustment, prior diagnosis of diabetes mellitus, sepsis, and the need for inotropic or vasopressor drugs.71 A prudent policy for the future would be not only to treat hypoglycemia promptly when it does occur, with attention to subsequent monitoring to avoid relapse or recurrence, but also to actively introduce strategies for predicting the risk of hypoglycemia and preventing it, especially when high risk is identified.10 The fear of hypoglycemia should not paralyze efforts to achieve better glycemic control in hospitalized patients.
UNANSWERED QUESTIONS AND VISION FOR THE FUTURE
On general wards, 38% of admitted patients may have hyperglycemia.72 As shown in the Leuven, Belgium, study, to achieve the target BG of less than 110 mg/dL in the intensive group in the surgical critical care unit, it was necessary to administer intravenous insulin infusion to essentially all patients. In a study that utilized continuous glucose monitoring, normoglycemia in patients in the intensive care unit was achieved as little as 22% of the time.73
An actively debated subject is how best to assess hospital performance in glycemic control (glucometrics). Hospitals need to show satisfactory control of variability between patients and within the treatment course of individual patients. That is, it is not sufficient to be satisfied with reasonable results of average blood glucose, using blood glucose as the unit of observation (where n is the number of blood glucose determinations). Alternatives are to use patient day or individual patient as a unit of observation (where n is the number of patient days and the number of patients, respectively). Time‐weighting methods are cumbersome but increase the validity of the averaging method used. When the patient is the unit of observation, possible measures include a per‐patient blood glucose average, percentage of blood glucose measurements with certain ranges, time spent within certain blood glucose ranges, or area under the curve of blood glucose versus time. Caveats about glucometrics pertain to both intravenous insulin infusion and also subcutaneous insulin management.74
Although awaiting additional evidence, diabetes experts have widely accepted the proposition that hospitals should focus on prevention of hyperglycemia as an important patient safety factor.75 Although the target range for glycemic control remains controversial, many students of the subject have endorsed the recommendations mentioned in the lead article in this issue, with the understanding that these criteria were developed from the results of the Leuven, Belgium, study, in which a whole blood glucose analyzer was used for measurement, and that the method of measurement of blood glucose must be considered in interpreting applicability of the target range at individual hospitals, many of which use plasma‐correlated methods yielding higher results. However, in new settings and for medical conditions that have not yet been rigorously evaluated by clinical trials, it is an unanswered question whether intensification of glycemic control can be achieved safely outside the critical care unit and, if so, what type of insulin therapy should be used and for what conditions the benefits would outweigh the risks and justify the costs.
Most inpatient management probably will continue to be conducted using subcutaneous injection therapy,7682 designed to match carbohydrate exposure through the appropriate use of analogs or conventional insulin products. One argument for the use of insulin analogs in the hospital, using basal‐prandial‐correction therapy, is the probability of reducing hypoglycemia and getting closer to target range control among patients who are eating but who are at risk for abrupt suspension of meals. Aggressive subcutaneous management strategies are likely to be most effective when standardized protocols, order sets, and informative computerized order entry systems gain widespread hospital acceptance.
If the importance of gaining glycemic control is highly time dependent and if hyperglycemia is uncontrolled, then a strong argument can be made for routine use of intravenous insulin infusion. For appropriately selected patients, intravenous insulin infusion is cost effective,83, 84 and its use can be extended to appropriate patients outside the critical care unit.8587 Many hospitals have protocols for intravenous insulin but use them only sporadically. For patients who already are in the intensive care setting, it is imperative to develop policies that require introduction of intravenous insulin infusion at a given glycemic threshold. On general wards that lack sufficient staffing to conduct intravenous insulin therapy, it is appropriate either to transfer candidate patients to a ward that has adequate staffing when medical condition requires improved control or to develop policies and procedures that will extend the use of intravenous insulin infusion to general wards. In the future, new technologies can be envisioned that will unburden nursing staff, making intravenous insulin infusion realizable as the treatment of choice for hemodynamically stable patients in most hospital settings. These technologies will include continuous monitoring of blood glucose, dose‐defining algorithms, and the eventual development of a fully automated closed‐loop system of monitoring and delivery that might automatically match insulin delivery to carbohydrate exposure and patient insulin sensitivity.8893
Until recently it had been argued that hospitalization was not the time in the life of a patient to insist on tight glycemic control. Hyperglycemia was understood to be a consequence of medical stress.1 It was well known that infection, sepsis, or other medical stress might exacerbate hyperglycemia or promote a diabetic crisis.25 Admittedly, the severity of hyperglycemia among patients who have diabetes was thought to predict the risk for hospitalization with infection as well as the outcome of the infectious condition.68 However, until recently strict glycemic control in the hospital was not strongly advocated because hypoglycemia might occur and might be directly and uniquely traceable to actions taken in the hospital.9, 10 Furthermore, the complications of diabetes were thought to be divided into acute metabolic emergencies and chronic tissue complications such as polyneuropathy, retinopathy, nephropathy, and macrovascular disease that would have evolved over a period longer than the duration of hospitalization, and the possibility that short‐term hyperglycemia might affect outcomes was considered unproven.
The purpose of this article is to define the specific populations, disorders, and hospital settings for which there now is strong evidence that short‐term glycemic control will affect the outcome of a course of hospital treatment.
PHYSIOLOGIC LINK BETWEEN HYPERGLYCEMIA AND ADVERSE OUTCOMES
Five years ago a caregiver would not have been likely to think of glycemic control as a contributing factor when considering specific complex problems such as pump failure or arrhythmia after cardiac surgery, long‐term mortality after myocardial infarction, acute renal failure, the need for transfusion during treatment of a complicated surgical illness, or prolonged dependence on a ventilator in the surgical ICU. Although it now known that these and other complications are linked to hospital hyperglycemia, the mechanisms of harm are several steps removed from the hyperglycemia itself. The causes of these adverse outcomes are multifactorial. The causal dependence of the injury on hyperglycemia is not easy to see. In fact, it required randomized prospectively designed trials to convincingly demonstrate the contributory role of hyperglycemia to these and other adverse outcomes.
Now that this link has been convincingly demonstrated, there is intense interest in discovering the probable mechanisms by which control of hyperglycemia and specifically the use of insulin might improve outcomes.1114 Mortality, predominantly sepsis related, was the primary outcome for which the Leuven, Belgium, report of 2001 on the surgical ICU showed improvement.15 Simplistically, in seeking a mechanism of benefit with respect to sepsis, it might be argued that if gross hyperglycemia were prevented in patients with surgical wounds, improvement of host defenses against infective organisms might be expected.1622 However, additional mechanisms of protection probably should be invoked, including those by which glycemic control and specifically insulin therapy affect endothelial function and the coagulation pathway, thus improving the ability of a patient to withstand and recover from sepsis. Insulin promotes beneficial nitric oxide synthase activation (e‐NOS) in capillary endothelium.2326 In patients with prolonged critical illness, intensive insulin therapy lowers ICAM‐1 levels, reflecting reduced endothelial activation. Whereas e‐NOS exerts a beneficial endothelial effect, hepatic iNOS activation is harmful. One proposed mechanism of benefit from adequate insulin therapy is suppression of excessive hepatic iNOS‐induced release of circulating NO, which might contribute to endothelial dysfunction, organ failure, and death.27
Additional proposed mechanisms of hyperglycemia‐induced harm to hospitalized patients, some potentially specifically reduced by insulin therapy, resemble those discussed in relation to macrovascular disease and include activation of inflammatory cytokines, matrix metalloproteinases, and adhesion molecules, and the adverse arrhythmogenic effects of elevated circulating nonesterified fatty acids (Figure 1).2834
CRITICAL WINDOW OF TIME
The results of several retrospectively or prospectively conducted single‐institution observational studies suggest there is a critical window of time within which clinicians must get it right, when attempting glycemic control or else jeopardize therapeutic goals, such as duration of remission in treatment of acute lymphocytic leukemia35 or avoidance of acute rejection in renal allograft surgery.36 Additionally, delayed risk of infection appears to be linked to previous glycemic control during specific early time frames surrounding surgery, renal transplantation, admission for trauma, and induction chemotherapy for leukemia (Table 1).3541 For patients who have diabetes, the potential to reduce the consequences of infections through intensified glycemic control probably begins prior to admission and in the hospital has still not been fully realized.4244
| Patients | Ascertainment of hyperglycemia | Delayed events among patients with early hyperglycemia |
|---|---|---|
| 100 postoperative uninfected diabetic patients undergoing elective surgery, monitored prospectively37 | First postoperative day | Postoperative nosocomial infection rate within 14 days was 2.7 times higher for patients having at least one BG > 220 mg/dL (33.3% vs. 11.5%). |
| 990 historical controls and 595 patients in the interventional group of postoperative cardiac diabetic patients40 | First 2 postoperative days | Incidence of deep sternal wound infection was reduced from 2.4% to 1.5% (P < 0.02) after introduction of protocol to maintain mean BG < 200 mg/dL. |
| 423 renal allograft recipients receiving their first cadaveric transplant36 | First 100 hours; first day. | A mean of 10.8 2.3 days after transplantation, 70% of patients developed postoperative infection, and after a mean of 7.7 2.6 days, 40% developed acute rejection. Every patient with mean BG over 200 mg/dL during the first 100 hours developed postoperative infection. On the first postoperative day the mean BG had been 248.4 mg/dL among those developing infection and 167.4 mg/dL among those without infection (P < .001), and the mean BG had been 270 mmol/L among those developing rejection and 194 mmol/L among those without rejection. |
| 516 trauma patients admitted to the ICU38 | Either of first 2 hospital days | Hyperglycemia 200 mg/dL was associated with a higher infection rate (32% vs. 22%, P = .04) and with greater mortality (34% vs. 13%, P < .0001) |
| 275 patients having lower‐extremity peripheral vascular surgery39 | First 48 hours | Postoperative infections within 30 days were 5.1 times more frequent in the top quartile for BG versus the lowest quartile (confidence interval 1.6‐17.1, P = .007). |
| 278 adult patients receiving induction chemotherapy for acute lymphocytic leukemia35 | First 30 days | Hyperglycemia defined as 2 BG 200 mg/dL was associated with a greater likelihood of sepsis (16.5% vs. 8.0%, P = .03) or any complicated infection (38.8% vs. 25.1%, P = .016), shorter duration of complete remission (24 vs. 52 months), and with shorter median survival (29 vs. 88 months, P = .001). |
KEY STUDIES SHOWING CLINICAL BENEFIT OF TIGHT GLYCEMIC CONTROL
A summary of several key studies that demonstrated the clinical benefit of tight glycemic control is shown in Table 2. These studies successfully separated the intensively and conventionally managed study groups according blood glucose. Although trials using glucose‐insulin‐potassium infusions (GIK) such that blood glucose was lowered have shown benefit for patients who have had myocardial infarctions4547 or cardiac surgery,48 not all GIK studies have yielded positive results. The negative results of the CREATE‐ECLA study suggest that GIK therapy per se is not beneficial unless it reduces blood glucose.49 In the setting of acute myocardial infarction, the DIGAMI 2 trial and the HI‐5 trials failed to achieve the intended separation between treatment groups.50, 51 It has been speculated that if insulin is delivered so as to not achieve normoglycemia, then hyperinsulinemia in the presence of hyperglycemia actually may be proinflammatory.52
| Population and/or setting and patients | Study design and/or intervention | Principal findings |
|---|---|---|
| Patients with diabetes mellitus and with hyperglycemia > 11 mmol/L or similar hyperglycemia without known diabetes who had had acute myocardial within the preceding 24 hours.4547 There were 620 patients, of whom 15 of the controls and 10 patients in the intensive group had no prior diagnosis of diabetes. | Prospective, randomized, controlled clinical trial. Controls received standard treatment. Treatment group received infusion of glucose‐insulin for at least 24 hours, followed by multiple injections of subcutaneous insulin for at least 3 months. | Overall mortality after 1 year was l9% in the insulin group compared to 26% among controls (P < .05). The most frequent cause of death of all patients was congestive heart failure. The benefit continued for at least 3.5 years, with an absolute reduction in mortality of 11%. |
| Diabetic cardiac surgery population.40, 5557 To date, 5510 cardiac surgery patients who were either admitted or discharged with the diagnosis of diabetes have been studied. | Prospective nonrandomized study of the effects of hyperglycemia and its pharmacologic reduction with intensive intravenous insulin regimens on outcomes. | The 3‐day average of perioperative BG (3‐BG) correlated with mortality (P < .0001, odds ratio 2.0 per 50 mg/dL increase in 3‐BG). Continuous intravenous insulin infusion independently reduced risk of death 60% (RR = 0.4, P < .001). Length of stay in the CABG population increased by 1 day for every increase of 50 mg/dL in 3‐BG. |
| Critically ill surgical patients receiving mechanical ventilation. Overall, 13% of 1548 participants had previously diagnosed diabetes. | Prospective, randomized, controlled clinical trial. Intravenous insulin infusion targeting BG 80‐110 mg/dL was initiated in the intensive group for BG > 110 mg/dL. Intravenous insulin infusion targeting BG 180‐200 was initiated in the conventional group for BG > 215 mg/dL. A whole‐blood glucose method using a gas analyzer was employed to determine arterial blood glucose. | In the group assigned to intensive insulin therapy mortality was reduced during intensive care from 8.0% with conventional treatment to 4.6% (P < .04), or a risk reduction of 42%. In the group remaining in the ICU for more than 5 days, mortality was reduced from 20.2% with conventional treatment to 10.6% with intensive insulin therapy; P = .005. The intensive group experienced reductions in overall in‐hospital mortality of 34%, in bloodstream infections of 46%, and in acute renal failure requiring dialysis or hemofiltration of 41%. Also reduced were the need for red‐cell transfusions, critical‐illness neuropathy, duration of mechanical ventilation, and length of stay in the ICU. |
| Critically ill medical patients. The intention to treat group included 1200 participants, of whom 16.9% had a history of diabetes.54 | Randomized controlled clinical trial, as above. | In the intensive group, in‐hospital mortality was not significantly reduced, and among the 433 who stayed in the ICU for less than 3 days, mortality was actually higher. However, in the intention‐to‐treat group there was reduction in newly acquired kidney injury, prolonged mechanical ventilation, and length of stay in the ICU and in the hospital. Among the 767 patients who stayed in the ICU for 3 or more days, intensive insulin therapy reduced in‐hospital mortality from 52.5% to 43.0%. |
| Patients within 24 hours of having an acute stroke and who had poststroke hyperglycemia. The results of the first 452 patients recruited to the GIST‐UK study showed that 15.3% had previously recognized diabetes.62 | Randomized controlled clinical trial. The intensive group received glucose‐potassium‐insulin (GKI) infusion, and the conventional group received saline infusion. | Although mean glucose declined in both groups, the GKI infusion safely achieved separation of groups by blood glucose. Outcomes are pending. |
The findings of the negative intensive insulin studies do not offset the evidence favoring glycemic control, derived from studies that actually achieved the lowering of blood glucose in the intensive groups, such as the successful prospectively designed trials in myocardial infarction or surgical or medical intensive care units15, 45, 47, 53, 54 and the long‐running, large, prospectively monitored Portland series utilizing insulin infusion for cardiac surgery,40, 5557 which have demonstrated the beneficial effects of euglycemia on mortality and morbidity, or the findings of Krinsley, reported elsewhere in this issue.58, 59 The well‐recognized correlation between outcomes of acute stroke and poststroke hyperglycemia has led to the design of a multicenter trial of glucose‐insulin‐potassium infusion for stroke, in which separation of groups by blood glucose has been achieved.6062 The success of GIK therapy in controlling hyperglycemia depends in part on the particular formulation of the infusion as it matches patient needs, and it is probable that insulin infusion following stroke is capable of safely achieving even tighter glycemic control than GIK.63 Intravenous insulin infusion therapy is more difficult to conduct than GIK therapy. However, because of concern about the proinflammatory and prothrombotic effects of hyperglycemia and recognition of the occasional failure of GIK infusions to control hyperglycemia and of the anti‐inflammatory, antithrombotic, and vasodilatory actions of insulin, there have been calls for additional trials of insulin infusions (as opposed to glucose‐insulin infusions) for both acute myocardial infarction and stroke.52, 64
HYPOGLYCEMIA
Serious or fatal sequelae of hypoglycemia are the principal safety risks in intensive insulin management.9, 65 Case ascertainment cannot be assured by glucose averaging methods but instead requires a method of searching for isolated episodes of hypoglycemia.10 One of the most dreaded consequences of nonfatal hypoglycemia is permanent impairment of intellectual function. Because many euglycemic medically ill patients experience alteration of sensorium while acutely ill, there is a risk that the consequences of an actual episode of severe hypoglycemia will be ascribed to other comorbidities, overlooking or misattributing the altered cognitive function that may persist at discharge to causes other than the obvious iatrogenic one. Because there is an increased risk of hypoglycemia during intensive insulin therapy, controversy has arisen over glycemic targets, especially among critically ill nonsurgical patients.54, 6669
On the other hand, the consequences of hypoglycemia during intensive intravenous insulin therapy in a surgical ICU were said to be negligible.15 In hospitalized elderly patients, hypoglycemia in association with increased mortality risk may not be an independent predictor.70 In the critical care unit, predictors of hypoglycemia are identifiable after the introduction of strict glycemic control that include not only insulin therapy but also CVVH treatment with bicarbonate substitution fluid, discontinuation of nutrition without insulin adjustment, prior diagnosis of diabetes mellitus, sepsis, and the need for inotropic or vasopressor drugs.71 A prudent policy for the future would be not only to treat hypoglycemia promptly when it does occur, with attention to subsequent monitoring to avoid relapse or recurrence, but also to actively introduce strategies for predicting the risk of hypoglycemia and preventing it, especially when high risk is identified.10 The fear of hypoglycemia should not paralyze efforts to achieve better glycemic control in hospitalized patients.
UNANSWERED QUESTIONS AND VISION FOR THE FUTURE
On general wards, 38% of admitted patients may have hyperglycemia.72 As shown in the Leuven, Belgium, study, to achieve the target BG of less than 110 mg/dL in the intensive group in the surgical critical care unit, it was necessary to administer intravenous insulin infusion to essentially all patients. In a study that utilized continuous glucose monitoring, normoglycemia in patients in the intensive care unit was achieved as little as 22% of the time.73
An actively debated subject is how best to assess hospital performance in glycemic control (glucometrics). Hospitals need to show satisfactory control of variability between patients and within the treatment course of individual patients. That is, it is not sufficient to be satisfied with reasonable results of average blood glucose, using blood glucose as the unit of observation (where n is the number of blood glucose determinations). Alternatives are to use patient day or individual patient as a unit of observation (where n is the number of patient days and the number of patients, respectively). Time‐weighting methods are cumbersome but increase the validity of the averaging method used. When the patient is the unit of observation, possible measures include a per‐patient blood glucose average, percentage of blood glucose measurements with certain ranges, time spent within certain blood glucose ranges, or area under the curve of blood glucose versus time. Caveats about glucometrics pertain to both intravenous insulin infusion and also subcutaneous insulin management.74
Although awaiting additional evidence, diabetes experts have widely accepted the proposition that hospitals should focus on prevention of hyperglycemia as an important patient safety factor.75 Although the target range for glycemic control remains controversial, many students of the subject have endorsed the recommendations mentioned in the lead article in this issue, with the understanding that these criteria were developed from the results of the Leuven, Belgium, study, in which a whole blood glucose analyzer was used for measurement, and that the method of measurement of blood glucose must be considered in interpreting applicability of the target range at individual hospitals, many of which use plasma‐correlated methods yielding higher results. However, in new settings and for medical conditions that have not yet been rigorously evaluated by clinical trials, it is an unanswered question whether intensification of glycemic control can be achieved safely outside the critical care unit and, if so, what type of insulin therapy should be used and for what conditions the benefits would outweigh the risks and justify the costs.
Most inpatient management probably will continue to be conducted using subcutaneous injection therapy,7682 designed to match carbohydrate exposure through the appropriate use of analogs or conventional insulin products. One argument for the use of insulin analogs in the hospital, using basal‐prandial‐correction therapy, is the probability of reducing hypoglycemia and getting closer to target range control among patients who are eating but who are at risk for abrupt suspension of meals. Aggressive subcutaneous management strategies are likely to be most effective when standardized protocols, order sets, and informative computerized order entry systems gain widespread hospital acceptance.
If the importance of gaining glycemic control is highly time dependent and if hyperglycemia is uncontrolled, then a strong argument can be made for routine use of intravenous insulin infusion. For appropriately selected patients, intravenous insulin infusion is cost effective,83, 84 and its use can be extended to appropriate patients outside the critical care unit.8587 Many hospitals have protocols for intravenous insulin but use them only sporadically. For patients who already are in the intensive care setting, it is imperative to develop policies that require introduction of intravenous insulin infusion at a given glycemic threshold. On general wards that lack sufficient staffing to conduct intravenous insulin therapy, it is appropriate either to transfer candidate patients to a ward that has adequate staffing when medical condition requires improved control or to develop policies and procedures that will extend the use of intravenous insulin infusion to general wards. In the future, new technologies can be envisioned that will unburden nursing staff, making intravenous insulin infusion realizable as the treatment of choice for hemodynamically stable patients in most hospital settings. These technologies will include continuous monitoring of blood glucose, dose‐defining algorithms, and the eventual development of a fully automated closed‐loop system of monitoring and delivery that might automatically match insulin delivery to carbohydrate exposure and patient insulin sensitivity.8893
- ,,.Stress‐induced hyperglycemia.Crit Care Clin.2001;17(1):107–124.
- ,,,,.Hyperosmolarity and acidosis in diabetes mellitus: a three‐year experience in Rhode Island.J Gen Intern Med.1991:495–502.
- ,,.Prognostic factors in the diabetic hyperosmolar state.J Am Geriatr Soc.1987;35:737–741.
- ,,.Predisposing factors for the diabetic hyperosmolar state.Arch Intern Med.1987;147:499–501.
- .The diabetic hyperosmolar state.Clin Geriatr Med.1990;6:797–806.
- ,,,,,.Bacteremia in adult diabetic patients.Diabetes Care.1991;14(2):89–94.
- ,,,,,.Influence of diabetes mellitus and glycaemic control on the characteristics and outcome of common infections.Diabet Med.1996:457–463.
- ,,.Diabetes and the risk of infection‐related mortality in the U.S.Diabetes Care.2001;24:1044–1049.
- ,,.Hypoglycemia in hospitalized patients.N Engl J Med.1986;315:1245–1250.
- ,,, et al.Hospital hypoglycemia: not only treatment but also prevention.Endocr Pract.2004;10(suppl 2):71–80.
- .Effect of insulin therapy on nonglycemic variables during acute illness.Endocr Pract.2004;10(suppl 2):63–70.
- .Molecular mechanisms by which metabolic control may improve outcomes.Endocr Pract.2004;10(suppl 2):57–62.
- ,,,,.Insulin infusion in acute illness.J Clin Invest.2005;115:2069–2072.
- ,,.Intensive insulin therapy in the intensive care unit: update on clinical impact and mechanisms of action.Endocr Pract.2006;12(suppl 3):14–21.
- ,,, et al.Intensive insulin therapy in critically ill patients.N Engl J Med.2001;345:1359–1367.
- ,,.Impaired granulocyte adherence. A reversible defect in host defense in patients with poorly controlled diabetes.Diabetes.1978;27:677–681.
- ,,.Impaired leukocyte function in patients with poorly controlled diabetes.Diabetes.1974;23(1):9–15.
- ,,, et al.The effect of diabetes mellitus on chemotactic and bactericidal activity of human polymorphonuclear leukocytes.Diabetes Res Clin Pract.1987;4:27–35.
- ,,,,.Polymorphonuclear leukocytes in non‐insulin‐dependent diabetes mellitus: abnormalities in metabolism and function.Ann Intern Med.1995;123:919–924.
- ,,,,.Agonist‐dependent failure of neutrophil function in diabetes correlates with extent of hyperglycemia.J Leukoc Biol.2001;70:395–404.
- ,,,,,.Insulin increases neutrophil count and phagocytic capacity after cardiac surgery.Anesth Analg.2002;94:1113–1119.
- ,,,.In vivo evidences that insulin regulates human polymorphonuclear neutrophil functions.J Leukoc Biol.2004;76:1104–1110.
- ,.Insulin‐stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells.J Clin Invest.1996;98:894–898.
- ,,,,.Insulin‐mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release.J Clin Invest.1994;94:1172–1179.
- ,.Effect of insulin on human aortic endothelial nitric oxide synthase.Metabolism.2000;49(2):147–50.
- ,.Nitric oxide, platelet function, myocardial infarction and reperfusion therapies.Heart Fail Rev.2003;8(1):47–54.
- ,,, et al.Intensive insulin therapy protects the endothelium of critically ill patients.J Clin Invest.2005;115:2277–2286.
- ,,, et al.Elevated circulating free fatty acid levels impair endothelium‐dependent vasodilation.J Clin Invest.1997;100:1230–1239.
- ,,, et al.Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti‐inflammatory effect?J Clin Endocrinol Metab.2001;86:3257–3265.
- ,,.The anti‐inflammatory and potential anti‐atherogenic effect of insulin: a new paradigm.Diabetologia.2002;45:924–930.
- ,,,.The potential influence of inflammation and insulin resistance on the pathogenesis and treatment of atherosclerosis‐related complications in type 2 diabetes.J Clin Endocrinol Metab.2003;88:2422–2429.
- ,,.The potential therapeutic role of insulin in acute myocardial infarction in patients admitted to intensive care and in those with unspecified hyperglycemia.Diabetes Care.2003;26:516–519.
- ,,.Insulin treatment improves the systemic inflammatory reaction to severe trauma.Ann Surg.2004;239:553–560.
- ,,, et al.Anti‐inflammatory and profibrinolytic effect of insulin in acute ST‐segment‐elevation myocardial infarction.Circulation.2004;109:849–854.
- .Relation between the duration of remission and hyperglycemia in induction chemotherapy for acute lymphocytic leukemia.Cancer.2004;100:1179–1185.
- ,,,,.Early peri‐operative glycaemic control and allograft rejection in patients with diabetes mellitus: a pilot study.Transplantation.2001;72:1321–1324.
- ,,, et al.Early postoperative glucose control predicts nosocomial infection rate in diabetic patients.J Parenter Enteral Nutr.1998;22(2):77–81.
- ,,,,.Relationship of early hyperglycemia to mortality in trauma patients.J Trauma.2004;56:1058–1062.
- ,,,,.Early post‐operative glucose levels are an independent risk factor for infection after peripheral vascular surgery. A retrospective study.Eur J Vasc Endovasc Surg.2004;5:520–525.
- ,,,.Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures.Ann Thorac Surg.1999;67:352–362.
- ,.Effects on outcome of in‐hospital transition from intravenous insulin infusion to subcutaneous therapy.Am J Cardiol.2006;98:557–564.
- ,,,.The impact of diabetes in patients with necrotizing soft tissue infections.Surg Infect.2005;6:427–438.
- ,,,.Infections in patients with diabetes mellitus.N Engl J Med.1999;341:1906–1912.
- ,,.Quantifying the risk of infectious diseases for people with diabetes.Diabetes Care.2003;26:510–513.
- ,,, et al.Randomized trial of insulin‐glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year.J Am Coll Cardiol.1995;26:57–65.
- ,,, et al.Effects of insulin treatment on cause‐specific one‐year mortality and morbidity in diabetic patients with acute myocardial infarction.Eur Heart J.1996;17:1337–1344.
- .Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus.DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group.BMJ.1997;314:1512–1515.
- ,,,,,.Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.Circulation.2004;109:1497–1502.
- .Effect of Glucose‐Insulin‐Potassium Infusion on Mortality in Patients With Acute ST‐Segment Elevation Myocardial Infarction: The CREATE‐ECLA Randomized Controlled Trial.JAMA.2005;293:437–446.
- ,,, et al.Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity.Eur Heart J.2005;26:650–661.
- ,,.The Hyperglycemia: Intensive Insulin Infusion In Infarction (HI‐5) Study: A randomized controlled trial of insulin infusion therapy for myocardial infarction.Diabetes Care.2006;29:765–770.
- .Inpatient diabetes: review of data from the cardiac care unit.Endocr Pract.2006;12(suppl 3):27–34.
- ,.Reduction of nosocomial infections in the surgical intensive‐care unit by strict glycemic control.Endocr Pract.2004;10(suppl 2):46–52.
- ,,, et al.Intensive insulin therapy in the medical ICU.N Engl J Med.2006;354:449–461.
- ,,.Glucose control lowers the risk of wound infection in diabetics after open heart operations.Ann Thorac Surg.1997;63:356–361.
- ,,, et al.Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting.J Thorac Cardiovasc Surg.2003;125:1007–1021.
- ,.Clinical effects of hyperglycemia in the cardiac surgery population: the Portland diabetic project.Endocr Pract.2006;12(suppl 3):22–26.
- .Effect of an intensive glucose management protocol on the mortality of critically ill adult patients.Mayo Clin Proc.2004;79:992–1000.
- .Decreased mortality of critically ill patients with the use of an intensive glycemic management protocol.Mayo Clin Proc.2003;78:1471–1478.
- ,,, et al.Admission glucose level and clinical outcomes in the NINDS rt‐PA Stroke. Trial.Neurology.2002;59:669–74.
- ,,,,,.Glucose potassium insulin infusions in the treatment of acute stroke patients with mild to moderate hyperglycemia: the Glucose Insulin in Stroke. Trial (GIST).Stroke.1999;30:793–799.
- ,,,.Poststroke hyperglycemia: natural history and immediate management.Stroke.2004;35(1):122–126.
- ,,,.IV insulin during acute cerebral infarction in diabetic patients.Neurology.2004;62:1441–1442.
- ,,,.Hyperglycemia, insulin, and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy.Stroke.2006;37(1):267–273.
- ,,.Hypoglycemia and cardiac arrest in a critically ill patient on strict glycemic control.Anesth Analg.2006;102:549–551.
- ,,.Strict glucose control in the critically ill.Br Med J.2006;332:865–866.
- .Intensive Insulin in Intensive Care.N Engl J Med.2006;354:516–518.
- ,.Counterpoint: Inpatient glucose management: a premature call to arms?Diabetes Care.2005;28:976–979.
- ,,,.Glucose control and mortality in critically ill patients.JAMA.2003;290:2041–2047.
- ,,, et al.Hypoglycemia as a predictor of mortality in hospitalized elderly patients.Arch Intern Med.2003;163:1825–1829.
- ,,, et al.Predisposing factors for hypoglycemia in the intensive care unit.Crit Care Med.2006;34:96–101.
- ,,,,,.Hyperglycemia: an independent marker of in‐hospital mortality in patients with undiagnosed diabetes.J Clin Endocrinol Metab.2002;87:978–982.
- ,,,.Intensive insulin therapy in the intensive care unit: assessment by continuous glucose monitoring.Diabetes Care.2006;29:1750–1756.
- ,,,.No patient left behind: evaluation and design of intravenous insulin infusion algorithms.Endocr Pract.2006;12(suppl 3):72–78.
- ,,, et al.Management of diabetes and hyperglycemia in hospitals.Diabetes Care.2004;27:553–591.
- ,,,.Eliminating Inpatient Sliding‐Scale Insulin: A reeducation project with medical house staff.Diabetes Care.2005;28:1008–1011.
- ,,.70/30 Insulin algorithm versus sliding scale insulin.Ann Pharmacother.2005;39:1606–1609.
- ,.Hospital management of hyperglycemia.Clin Diabetes.2004;22(2):81–88.
- ,.Subcutaneous insulin therapy in the hospital setting: issues, concerns, and implementation.Endocr Pract.2004;10(suppl 2):81–88.
- ,,,,.Hyperglycemia in the hospital.Diabetes Spectr.2005;18(1):20–27.
- .Insulin Analogues.N Engl J Med.2005;352:174–183.
- .Insulin management of diabetic patients on general medical and surgical floors.Endocr Pract.2006;12(suppl 3):86–90.
- ,,, et al.Improved perioperative glycemic control by continuous insulin infusion under supervision of an endocrinologist does not increase costs in patients with diabetes.Endocr Pract.2004;10(2):112–118.
- ,,.Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland Diabetic Project.Endocr Pract.2004;10(suppl 2):21–33.
- ,,,.New insulin infusion protocol improves blood glucose control in hospitalized patients without increasing hypoglycemia.J Qual Patient Saf.2005;31:141–147.
- ,,,,.Optimizing hospital use of intravenous insulin therapy: improved management of hyperglycemia and error reduction with a new nomogram.Endocr Pract.2005;11:240–253.
- ,,,,.Implementation of a new intravenous insulin method on intermediate‐care units in hospitalized patients.Diabetes Educ.2005;31:818–823.
- ,,.Clinical results of an updated insulin infusion protocol in critically ill patients.Diabetes Spectr.2005;18(3):188–191.
- ,,.Glucommander: A computer‐directed intravenous insulin system shown to be safe, simple, and effective in 120,618 h of operation.Diabetes Care.2005;28:2418–2423.
- ,,, et al.Improving hyperglycemia management in the intensive care unit: preliminary report of a nurse‐driven quality improvement project using a redesigned insulin infusion algorithm.Diabetes Educ.2006;32:394–403.
- ,,, et al.Performance of a dose‐defining insulin infusion protocol among trauma service ICU admissions.Diabetes Technol Ther.2006;8:476–488.
- ,,, et al.A simple insulin‐nutrition protocol for tight glycemic control in critical illness: development and protocol comparison.Diabetes Technol Ther.2006;8:191–206.
- ,,, et al.Evaluation of the impact of chiropodist care in the secondary prevention of foot ulcerations in diabetic subjects.Diabetes Care.2003;26:1691–1695.
- ,,.Stress‐induced hyperglycemia.Crit Care Clin.2001;17(1):107–124.
- ,,,,.Hyperosmolarity and acidosis in diabetes mellitus: a three‐year experience in Rhode Island.J Gen Intern Med.1991:495–502.
- ,,.Prognostic factors in the diabetic hyperosmolar state.J Am Geriatr Soc.1987;35:737–741.
- ,,.Predisposing factors for the diabetic hyperosmolar state.Arch Intern Med.1987;147:499–501.
- .The diabetic hyperosmolar state.Clin Geriatr Med.1990;6:797–806.
- ,,,,,.Bacteremia in adult diabetic patients.Diabetes Care.1991;14(2):89–94.
- ,,,,,.Influence of diabetes mellitus and glycaemic control on the characteristics and outcome of common infections.Diabet Med.1996:457–463.
- ,,.Diabetes and the risk of infection‐related mortality in the U.S.Diabetes Care.2001;24:1044–1049.
- ,,.Hypoglycemia in hospitalized patients.N Engl J Med.1986;315:1245–1250.
- ,,, et al.Hospital hypoglycemia: not only treatment but also prevention.Endocr Pract.2004;10(suppl 2):71–80.
- .Effect of insulin therapy on nonglycemic variables during acute illness.Endocr Pract.2004;10(suppl 2):63–70.
- .Molecular mechanisms by which metabolic control may improve outcomes.Endocr Pract.2004;10(suppl 2):57–62.
- ,,,,.Insulin infusion in acute illness.J Clin Invest.2005;115:2069–2072.
- ,,.Intensive insulin therapy in the intensive care unit: update on clinical impact and mechanisms of action.Endocr Pract.2006;12(suppl 3):14–21.
- ,,, et al.Intensive insulin therapy in critically ill patients.N Engl J Med.2001;345:1359–1367.
- ,,.Impaired granulocyte adherence. A reversible defect in host defense in patients with poorly controlled diabetes.Diabetes.1978;27:677–681.
- ,,.Impaired leukocyte function in patients with poorly controlled diabetes.Diabetes.1974;23(1):9–15.
- ,,, et al.The effect of diabetes mellitus on chemotactic and bactericidal activity of human polymorphonuclear leukocytes.Diabetes Res Clin Pract.1987;4:27–35.
- ,,,,.Polymorphonuclear leukocytes in non‐insulin‐dependent diabetes mellitus: abnormalities in metabolism and function.Ann Intern Med.1995;123:919–924.
- ,,,,.Agonist‐dependent failure of neutrophil function in diabetes correlates with extent of hyperglycemia.J Leukoc Biol.2001;70:395–404.
- ,,,,,.Insulin increases neutrophil count and phagocytic capacity after cardiac surgery.Anesth Analg.2002;94:1113–1119.
- ,,,.In vivo evidences that insulin regulates human polymorphonuclear neutrophil functions.J Leukoc Biol.2004;76:1104–1110.
- ,.Insulin‐stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells.J Clin Invest.1996;98:894–898.
- ,,,,.Insulin‐mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release.J Clin Invest.1994;94:1172–1179.
- ,.Effect of insulin on human aortic endothelial nitric oxide synthase.Metabolism.2000;49(2):147–50.
- ,.Nitric oxide, platelet function, myocardial infarction and reperfusion therapies.Heart Fail Rev.2003;8(1):47–54.
- ,,, et al.Intensive insulin therapy protects the endothelium of critically ill patients.J Clin Invest.2005;115:2277–2286.
- ,,, et al.Elevated circulating free fatty acid levels impair endothelium‐dependent vasodilation.J Clin Invest.1997;100:1230–1239.
- ,,, et al.Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti‐inflammatory effect?J Clin Endocrinol Metab.2001;86:3257–3265.
- ,,.The anti‐inflammatory and potential anti‐atherogenic effect of insulin: a new paradigm.Diabetologia.2002;45:924–930.
- ,,,.The potential influence of inflammation and insulin resistance on the pathogenesis and treatment of atherosclerosis‐related complications in type 2 diabetes.J Clin Endocrinol Metab.2003;88:2422–2429.
- ,,.The potential therapeutic role of insulin in acute myocardial infarction in patients admitted to intensive care and in those with unspecified hyperglycemia.Diabetes Care.2003;26:516–519.
- ,,.Insulin treatment improves the systemic inflammatory reaction to severe trauma.Ann Surg.2004;239:553–560.
- ,,, et al.Anti‐inflammatory and profibrinolytic effect of insulin in acute ST‐segment‐elevation myocardial infarction.Circulation.2004;109:849–854.
- .Relation between the duration of remission and hyperglycemia in induction chemotherapy for acute lymphocytic leukemia.Cancer.2004;100:1179–1185.
- ,,,,.Early peri‐operative glycaemic control and allograft rejection in patients with diabetes mellitus: a pilot study.Transplantation.2001;72:1321–1324.
- ,,, et al.Early postoperative glucose control predicts nosocomial infection rate in diabetic patients.J Parenter Enteral Nutr.1998;22(2):77–81.
- ,,,,.Relationship of early hyperglycemia to mortality in trauma patients.J Trauma.2004;56:1058–1062.
- ,,,,.Early post‐operative glucose levels are an independent risk factor for infection after peripheral vascular surgery. A retrospective study.Eur J Vasc Endovasc Surg.2004;5:520–525.
- ,,,.Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures.Ann Thorac Surg.1999;67:352–362.
- ,.Effects on outcome of in‐hospital transition from intravenous insulin infusion to subcutaneous therapy.Am J Cardiol.2006;98:557–564.
- ,,,.The impact of diabetes in patients with necrotizing soft tissue infections.Surg Infect.2005;6:427–438.
- ,,,.Infections in patients with diabetes mellitus.N Engl J Med.1999;341:1906–1912.
- ,,.Quantifying the risk of infectious diseases for people with diabetes.Diabetes Care.2003;26:510–513.
- ,,, et al.Randomized trial of insulin‐glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year.J Am Coll Cardiol.1995;26:57–65.
- ,,, et al.Effects of insulin treatment on cause‐specific one‐year mortality and morbidity in diabetic patients with acute myocardial infarction.Eur Heart J.1996;17:1337–1344.
- .Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus.DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group.BMJ.1997;314:1512–1515.
- ,,,,,.Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.Circulation.2004;109:1497–1502.
- .Effect of Glucose‐Insulin‐Potassium Infusion on Mortality in Patients With Acute ST‐Segment Elevation Myocardial Infarction: The CREATE‐ECLA Randomized Controlled Trial.JAMA.2005;293:437–446.
- ,,, et al.Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity.Eur Heart J.2005;26:650–661.
- ,,.The Hyperglycemia: Intensive Insulin Infusion In Infarction (HI‐5) Study: A randomized controlled trial of insulin infusion therapy for myocardial infarction.Diabetes Care.2006;29:765–770.
- .Inpatient diabetes: review of data from the cardiac care unit.Endocr Pract.2006;12(suppl 3):27–34.
- ,.Reduction of nosocomial infections in the surgical intensive‐care unit by strict glycemic control.Endocr Pract.2004;10(suppl 2):46–52.
- ,,, et al.Intensive insulin therapy in the medical ICU.N Engl J Med.2006;354:449–461.
- ,,.Glucose control lowers the risk of wound infection in diabetics after open heart operations.Ann Thorac Surg.1997;63:356–361.
- ,,, et al.Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting.J Thorac Cardiovasc Surg.2003;125:1007–1021.
- ,.Clinical effects of hyperglycemia in the cardiac surgery population: the Portland diabetic project.Endocr Pract.2006;12(suppl 3):22–26.
- .Effect of an intensive glucose management protocol on the mortality of critically ill adult patients.Mayo Clin Proc.2004;79:992–1000.
- .Decreased mortality of critically ill patients with the use of an intensive glycemic management protocol.Mayo Clin Proc.2003;78:1471–1478.
- ,,, et al.Admission glucose level and clinical outcomes in the NINDS rt‐PA Stroke. Trial.Neurology.2002;59:669–74.
- ,,,,,.Glucose potassium insulin infusions in the treatment of acute stroke patients with mild to moderate hyperglycemia: the Glucose Insulin in Stroke. Trial (GIST).Stroke.1999;30:793–799.
- ,,,.Poststroke hyperglycemia: natural history and immediate management.Stroke.2004;35(1):122–126.
- ,,,.IV insulin during acute cerebral infarction in diabetic patients.Neurology.2004;62:1441–1442.
- ,,,.Hyperglycemia, insulin, and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy.Stroke.2006;37(1):267–273.
- ,,.Hypoglycemia and cardiac arrest in a critically ill patient on strict glycemic control.Anesth Analg.2006;102:549–551.
- ,,.Strict glucose control in the critically ill.Br Med J.2006;332:865–866.
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